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The objective of the HOT study, an international, prospective, randomised study is to determine the optimal level of the blood pressure under treatment, in linked with the lowest cardiovascular mortality and morbidity. The target diastolic blood pressure of 80, 85 and 90 mmHg was determined at the randomisation. In order to reach the target blood pressure, a strategy of treatment was determined: the 1st step was felodipine (a long acting dihydropyridine) and the next steps (if the blood pressure reduction is not enough) propose the addition of different therapeutic classes and/or the increase of each drug doses. The available data after 2 years of the patients follow-up allow us to evaluate the incidence of the reported side effects according to the target blood pressure assigned by randomisation and the number of hypertension drugs used to reach these targets. The percentage of patients with at least one side effect at 12 and 24 months of follow-up are respectively: for the target group DBPor = 90 mmHg: 9.2% versus 6%; for the target group DBPor = 85 mmHg: 8% versus 4.4%; for the target group DBPor = 80 mmHg: 7.9% versus 4.9%. The overall tolerability is not influenced by the target diastolic blood pressure but depends on the number of hypertension drugs used. At 24 months, 2.8% of patients are under monotherapy; 7% under bitherapy and 9.8% under tritherapy. The incidence of the side effects decreases after the 1st year, but slower than between the third months and the first year. There is an influence of the region on the incidence of the side effects, the south European countries describing more side effects than France or the north European countries. This seems to be linked with a perception of the side effects more than with a higher rate. In conclusion, these results confirm the possibility to reach a targeted blood pressure using a predetermined strategy without increasing dramatically the incidence of the side effects.

The aim of this study was to evaluate the antihypertensive effect of drugs according to the initial ambulatory blood pressure (BP) level. After a 15-day placebo run-in period, 105 patients with moderate essential hypertension (mean age, 52 years) underwent 24-h BP monitoring (spacelabs: 1 measure/15 min). Patients were subdivided into two groups: the "High" group, with 24-h mean values of systolic BP (SBP) > 137 or diastolic BP (DBP) > 87 mm Hg, and the "Low" group, with SBP < or = 137 and DBP < or = 87 mm Hg. All patients received, in a random and double-blind design, either bisoprolol (10 mg q.d.) or lisinopril (20 mg q.d.) for 8 weeks. At the end of this active treatment period, office and ambulatory BP measurements were performed. Casual measurements revealed similar BP decreases in all subgroups receiving bisoprolol and lisinopril; BP monitoring showed that the antihypertensive effect depended on the baseline mean 24-h value; -15/-12 mm Hg for bisoprolol and -18/-13 mm Hg for lisinopril in the High group; -7/-6 mm Hg for bisoprolol and -6/-6 mm Hg for lisinopril in the Low group. This study shows that the antihypertensive effect depended on initial ambulatory BP values, with a lower BP decrease in the Low group. Assessment of the antihypertensive effect on ambulatory BP is useful in clinical trials.

International, prospective, randomized HOT study aims to determine the optimal BP level under treatment in order to reduce at the most the cardiovascular morbidity/mortality. Defined by randomization, the level to obtain is DBPor = 80, 85, 90 mmHg. The treatment is started by felodipine 5 mg/day then, if necessary, a bitherapy is prescribed and then, if necessary, a tritherapy. 19,193 patients have been included (BP at randomization 170 +/- 15/105 +/- 4 mmHg). After 1 year treatment, it is possible to search for the influence on the clinical tolerance of sex, age, BP goal, geographic area, time and treatment. The percentage of patients with side effects by BP goals and by treatment type are, during the time and in different geographic areas, the following (NE/Northern Europe = Norway, Switzerland, Belgium, Hungary, Sweden, Denmark, Finland, The Netherlands, UK, Germany, Austria; SE/Southern Europe = Italy, Spain, Greece): [table: see text] The target BP and age don't nearly influence the clinical tolerance. The side effects reported by the physicians are more numerous at the treatment start than at longeur terme. That is due to the therapeutic modifications of the physicians or to a better acceptation of the drugs by the patients or to a real disappearance of the side effects. Reported side effects are more frequent in Southern Europe, France than Northern Europe and more frequent among women that men. The incidence of side effects is proportional to the number of prescribed drugs. Time and the number of antihypertensive drugs appear as the most important factors.

This study was designed to assess the compliance of hypertensive patients with a once-daily regimen of the angiotensin converting enzyme (ACE) inhibitor trandolapril and to evaluate the antihypertensive efficacy of the drug in relation to the time interval between taking the final dose and measuring the blood pressure (BP).After a 2-week wash-out period, hypertensive patients, recruited by cardiologists, received trandolapril 2 mg once daily in the morning for 4 weeks.In order to assess compliance, each patient's supply of trandolapril capsules was presented in a pillbox that incorporated in its lid a microprocessor that recorded the date and time of each occasion that it was opened. BP was measured using validated semi-automatic devices, at the end of both the wash-out and the treatment period.A total of 590 patients entered the study. Compliance data were evaluable for 501 patients. Overall compliance, defined as the ratio of the number of openings recorded to the number of doses prescribed was less than 80, 80-100, and more than 100% in 17, 63 and 20% of patients, respectively. The average number (+/- SD) of missed doses was 4.5 +/- 8 (median 2). The average interval between successive openings was 25 h 07 min mean +/- 13 h (median 24 h). The average number of delayed doses (a delayed dose being defined as the box being opened 25-36 h after the previous occasion) was 5.6 +/- 3 (median 6). Patients living in the Paris area had more forgotten and delayed doses than those living in the provinces (7.9 versus 3.8 forgotten; P0.0001 and 6.3 versus 5.5 delayed; P0.005). Doses were forgotten and delayed more often during weekends than on weekdays. The greatest number of delayed doses occurred in those patients under 60 years of age (6.0 versus 5.2; P0.01). Decreases in systolic blood pressure (SBP and diastolic blood pressure (DBP) were 20.3/12.8 mmHg, for patients whose final drug was taken on the same day as the BP measurement, and 18.9/11.2 mmHg for patients whose final dose was taken on the previous day.Electronic compliance monitoring allows refined analysis of the behaviour of hypertensive patients. In this study doses were missed and delayed frequently during the first month of treatment, depending on the patient's lifestyle.

The objective of this study was to evaluate the relationship between non-invasive ambulatory blood pressure variability and cardiac baroreflex sensitivity in hypertensive patients.Ambulatory blood pressure measurements (15-min intervals for 24 h) and continuous blood pressure measurements (Finapres, 20 min at rest after a 10-min resting period) were performed in 123 untreated hypertensives (resting diastolic blood pressureor = 90 mmHg; 80 males, 43 females; mean +/- SD age 49 +/- 12 years, range 19-73). Fourier series were used to model 24-h blood pressure profiles (four harmonics). Ambulatory blood pressure variability was assessed by determination of the residuals in each 24-h blood pressure profile (measured minus predicted pressures). Resting blood pressure variability was defined as the SD of the mean Finapres value. Baroreflex sensitivity was evaluated by automatic detection of blood pressure and pulse interval sequences ofor = 3 beats when systolic blood pressure and pulse interval sequences changed in the same direction (increase or decrease: 1 mmHg for systolic blood pressure and 4 ms for RR interval), and was assessed as the slope of the regression line for each sequence.Ambulatory systolic blood pressure variability increased with age (r = 0.28*) and systolic pressure (r = 0.44**). Baroreflex sensitivity (increasing systolic pressure/pulse interval) decreased significantly with age (r = -0.48**) and systolic pressure (r = -0.23**), and was significantly related to increased ambulatory blood pressure variability (r = -0.33**). In a multivariate stepwise analysis the relationship between ambulatory blood pressure variability and baroreflex sensitivity (increasing systolic pressure/pulse interval) was statistically independent of age and systolic pressure (R = 0.55, P0.001); this relationship was not observed with the corresponding decreasing sequence.This study shows that in uncomplicated hypertension, ambulatory blood pressure variability is related to baroreflex sensitivity independently of the blood pressure level. This finding has prognostic implications for this non-invasive measurement, which needs to be confirmed by large longitudinal studies.

The objective of the MACH1 study (MEMS for the Assessment of Compliance of Hypertensives) was to evaluate the real behaviour of patients in relation to antihypertensive treatment administered as a single daily dose. After a 2-week period during which no other antihypertensive was allowed to be administered, 590 patients with mild-to-moderate hypertension received 2 mg of trandolapril as a single daily dose in the morning between 7:00 a.m. and 9:00 a.m. for 4 weeks. Treatment was packaged in electronic pillboxes recording the date and time of each opening. Various profiles were distinguished on the basis of the individual chronograms for the 501 patients able to be analysed in terms of compliance, and as a function of the deviations observed in relation to the treatment regimen prescribed. One hundred and two patients (20%) omitted more than 20% of the prescribed doses, either consecutive doses or scattered throughout the month of treatment; these patients were referred to as "omitters". The other patients were classified according to the scatter of openings in relation to the mean time of the dose: 10 "metronome" patients (2%), 126 "regular" patients (25%), 221 "irregular" patients (44%) and 42 "anarchic" patients (8%). Irregularities of dose times were more frequent on public holidays than on week days and in patients living in Paris or the Paris region. "Metronome" patients were older than the overall patient population. The use of an electronic pillbox could allow the attending physician to more adequately adapt his therapeutic approach and management of specific problems of compliance observed in hypertensive patients.

The objective is to study the relation between left ventricular (LV) effect (index of LV mass (LVMI) and index of inotropic state) and arterial compliance determined but the proximal aortic pressure waveform and by the carotid femoral pulse wave velocity.72 untreated hypertensives; systolic blood pressure (SBP) 170 +/- 18 mmHg/diastolic blood pressure (DBP); heart rate: 69 +/- 9 batt/min; age: 48 +/- 13 years; duration of hypertension 4.6 +/- 4.8 years; sex ratio 49 M/23 F.Proximal aortic pressure waveform (carotid artery) was studied by applanation tonometry. We derived the index of amplification (AI = Pmax-Pinflex)/PP, %), pulse pressure (PP), the maximum rate of rise of pressure (dpdt, mmHg.s-1). Echocardiography was used to define the index of LV mass (VLMI), end systolic volume (ESV), end systolic stress (ESS), myocardial contractile force (ESS/ESV), inotropic state (SBP/ESV). Carotid-femoral pulse wave velocity was determined by mechanogram (PWW m/s).1. Relationship of physiological changes of AI and SDA to age, height, PP, DBP, PWV, and LVMI were observed in table I (r-Pearson cor. coefficient, *p 0.05; **: p0.001). [table: see text] In stepwise regression analysis, even allowing for BP, age, and height, there was no relationship between LVMI and the index of aortic amplification (AI). 2. In the subjects with LVH (LVMI110 g/m2) we found a bimodal distribution of the AI which defines two groups in agreement with the Murgo Classification. [table: see text] In type B, where AI is weaker, the indices of aortic rigidity are reduced, there is an increased ESS and a paradoxal fall in LV performances.Analysis of proximal aortic pressure waveform don't allow to predict index of LV mass. These results suggest that in the sphere of LV aortic compiling the reduction of LV function contributes to modification of the BP waveform with diminution of dpdt and the index of amplification.

Relationships between baroreflex sensitivity (BRS) and arterial distensibility are evaluated by continuous measurement of blood pressure (Finapres) and carotid-femoral pulse wave velocity measurement (PWV); 73 subjects are recruited on WHO criteria (age: 48 +/- 13). An ambulatory measurement of BP is also performed to evaluate the mean BP 24 level. The BRS is evaluated at rest during 20 min of acquisition data in a lying position, using a dedicated software [(automatic detection by of BP sequences were 3 or more systolic BP and RR interval increased of 1 mmHg for SBP and 4 ms for RR (PS+/RR+) or decreased (PS-/RR-)]. The BRS is the slope of the regression line between SBP and RR interval of each sequences (if correlation coefficient0.95).resting BP: SBP/DBP = 170 +/- 12 mmHg. HR 72 +/- 15 batt/min, PWV = 10.8 +/- 3.2 m/s. Mean BRS is 8.2 +/- 3.8 for PS+/RR+ and 8.7 +/- 3.8 ms/mmHg PS-/RR-. The coefficient of correlation (Pearson) between PWV and BRS is -0.59* for PS+/RR+ and -0.41* for PS-/RR- (*: p0.01). In multivariate analyses, these relations were statistically independent of age and BP for the sequences PS+/RR+ but not for the sequences PS-/RR- suggesting a predominant vagal alteration in hypertensive subjects associated with the alteration of carotido-femoral pulse wave velocity.

This double-blind placebo-controlled study was designed to compare the efficacy of benazepril 10 mg (BZ 10) and the low-dose combination benazepril 5 mg/hydrochlorothiazide 6.25 mg (BZ + HCTZ) on exercise blood pressure in 71 patients with mild to moderate hypertension (diastolic blood pressure 95 to 114 mmHg at the end of a 2 week placebo run-in). A significant fall of systolic (SBF) and diastolic (DBP) blood pressure at rest was seen after a 4-week treatment period in the two active groups (-21.9/-10.3 mmHg with BZ 10, -19.5/-11.2 mmHg with BZ + HCTZ) and was greater in these two groups than in the placebo group (-7.5/-2.5 mmHg, p0.01). For each level of the exercise test on bicycle ergometer, SBP falls seen after 1 month were significant in the two active groups (from -15 to -23 mmHg depending on the level and treatment group). The evolution of the SBP/heart rate slope was significantly different among the two active groups in favour of the BZ 10 regimen. The exercise test proved to be a valuable tool to show any difference between two treatments with comparable efficacy on SBP/DBP at rest.

Ambulatory blood pressure monitoring (ABPM) is a particularly useful method for evaluating the effects of antihypertensive drugs. ABPM allows the therapeutic effect of an agent to be assessed continually by a large number of measurements, and the greater number of readings contributes to the higher degree of reproducibility associated with ABPM compared to other methods for measuring blood pressure. ABPM also enable measurements to be taken in "real-life" situations and removes the problem of observer bias. The number of patients required for clinical studies can be significantly reduced by using ABPM. It is still essential, however, to identify "white coat" subjects, placebo responders, and patients who do not respond to the treatment. ABPM studies have demonstrated that the novel dihydropyridine calcium antagonist, lacidipine, significantly reduces both systolic and diastolic blood pressures over a 24-h period, both during the day and at night. Furthermore, although the trough-to-peak ratios of many calcium antagonists have been shown to fall below the recommended level of 50%, lacidipine has a ratio above 60%. Other ABPM studies have also shown that lacidipine can correct the 'early morning increase' in blood pressure without effecting the 24-h nycthemeral profile.

The high incidence of cardiovascular morbidity and mortality in hypertensive patients with left ventricular hypertrophy shows the great interest in understanding the pathophysiology of this process. Many reports suggest the role of catecholamines in generating left ventricular hypertrophy. The aim of this study is to evaluate the effect of labetalol on myocardial norepinephrine content in hypertensive subjects with left ventricular hypertrophy by using an isotopic norepinephrine marker, the 123I-meta-iodobenzylguanidine (123I-MIBG). Eight male and female hypertensive patients with left ventricular hypertrophy were investigated after a 30 day placebo period. Resting, ambulatory and effort blood pressure was measured. Echocardiographic parameters allowed measure of left ventricular mass index according to Devereux. And we considered left ventricular hypertrophy as left ventricular mass index greater than 120 g/m2. Cardiac and mediastinal radioactivity is detected 4 h after a 4 mCi i.v. injection of 123I-MIBG and MIBG myocardial uptake is definite as the cardiac/mediastinal ratio (N : 1.78 +/- 0.19). All subjects received at the beginning of the study (D0) 2 tablets of labetalol 200 mg, increased to 4 tablets if diastolic blood pressure during follow-up remained above 95 mmHg. Patients again underwent these explorations after 3 months of treatment (D90). Labetalol decreases in considerable manner MIBG myocardial uptake as it has been shown that it decreases tissular norepinephrine content in experimental studies. Therefore, MIBG myocardial uptake seems to be a reliable tool in evaluating drugs effect on cardiac sympathetic nervous system.

The results of several studies, mostly without controls, have suggested that betablockers, administered at progressively increasing doses, may be beneficial in cardiac failure. Based on this hypothesis, betablockers with a peripheral vasodilator effect, such as Nebivolol, could be particularly valuable in this indication. A preliminary study of its tolerance, haemodynamic and neurohormonal effects was carried out with a noninvasive methodology in 12 patients with cardiac failure in sinus rhythm, 8 men and 4 women (average age 53 +/- 12 years), all of whom had Class III or IV symptoms according to the NYHA Classification. The protocol had 2 phases: the first was an open phase during which Nebivolol was administered at a dose of 1 mg/day for 48 hours then 2.5 mg/day for 72 h. In the second phase, the patients were randomly separated into 2 groups, one to receive placebo and the other 2.5 mg for one week then 5 mg of Nebivolol for the 5 remaining weeks. The heart rate decreased significantly from 70 +/- 3 to 63 +/- 4 beats/min (p0.01) with Nebivolol 1 mg/day without further slowing at the 2.5 mg dosage. During the randomised phase, the heart rate remained stable in the Nebivolol group but increased to its initial value in the group given placebo. No aggravation of symptoms was observed in the Nebivolol group. No significant changes in cardiac output, parameters of cardiac loading or contractility could be demonstrated after 6 weeks' treatment. During submaximal exercise testing, plasma concentrations of catecholamines and atrial natriuretic factor tended to be higher with Nebivolol than with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Although there has never been a consensus about the presentation and analysis of the results of ambulatory blood pressure recordings, it is important to define the stages and useful means both for studying individual and groups of recordings (therapeutic trials): individual recordings: edition of results, 24 hour display, quantification of the blood pressure over predefined periods, comparison with reference values; therapeutic trials: verification of the quality of the recordings (consecutive hours without measurements, artefacts), preparation of the results for analysis (grouped in hourly mean values), search for confusing factors and non-adherence to the protocol, analysis of efficacy over 24 hours and predefined periods, partial studies (non-responders, normalisation of blood pressure with respect to reference values, control of efficacy over more than 24 hours...). All these stages must be predefined in the study protocol.