Lack of effect of percutaneous transluminal renal angioplasty on nocturnal hypotension in renovascular hypertensive patients.

OBJECTIVE: To investigate whether nocturnal blood pressure fall is blunted in renovascular hypertension and can therefore be used as a diagnostic criterion for this condition. METHODS: In 14 renovascular hypertensive patients (age 43.8+/-2.1 years, mean+/-SEM, clinic blood pressure 173.6+/-3.7 mmHg systolic and 109.0+/-2.0 mmHg diastolic) and in 14 age- and blood pressure-matched essential hypertensive controls 24 h ambulatory blood pressure was measured after washout from drug treatment, during angiotensin converting enzyme inhibitor treatment and, in renovascular hypertension, also after percutaneous transluminal renal angioplasty. RESULTS: The 24 h average systolic and diastolic blood pressures were 146.4+/-5.7 and 97.5+/-3.6 mmHg in renovascular and 144.3+/-1.2 and 98.0+/-2.2 mmHg in essential hypertensive patients. The angiotensin converting enzyme inhibitor treatment reduced 24 h average systolic and diastolic blood pressures by 8.5% and 9.7% in the renovascular and by 8.3% and 10.8% in the essential hypertensive group. Greater systolic and diastolic blood pressure reductions (-18.2% and -18.1%) were observed in renovascular hypertensive patients after percutaneous transluminal renal angioplasty. Blood pressure fell by about 10% during the night and the fall was similar in renovascular and in essential hypertensive patients. In the former group, nocturnal hypotension was similar after washout, during angiotensin converting enzyme inhibitor treatment and after percutaneous transluminal renal angioplasty. Similar results were obtained for nocturnal bradycardia. CONCLUSIONS: Nocturnal blood pressure fall is equally manifest in renovascular and essential hypertension. The removal of the renal artery stenosis and blood pressure normalization do not enhance this phenomenon. Nocturnal hypotension seems therefore to be unaffected by renovascular hypertension.

Permanent blood pressure control over the 24 h by trandolapril.

Noninvasive ambulatory blood pressure monitoring (ABPM) has proved to be an innovative tool for the assessment of the efficacy of antihypertensive drugs. It enables evaluation of the magnitude of the drug-related blood pressure fall and also of the duration of this effect throughout 24 h. Moreover, ambulatory blood pressures have advantages compared to office blood pressure: they are not affected by the white coat effect occurring at the time of the doctor's visit, are devoid of a placebo effect, are more reproducible than occasional clinic measurements, and may yield important information on the prognosis of hypertensive patients. Ambulatory blood pressure recordings were used to test the antihypertensive effect of a novel angiotensin converting enzyme, trandolapril, in 62 mild to moderate essential hypertensive outpatients. After a 4 week wash-out, period, patients were randomized to 2 mg trandolapril or placebo for 6 weeks. A 4-week wash-out period was scheduled at the end of the treatment period. Ambulatory blood pressure recordings were performed at the end of each period, starting in the morning. Trandolapril (n = 31) significantly reduced 24 h systolic and diastolic blood pressure as compared to pre- and posttreatment periods and to placebo (n = 17). The reduction involved both the daytime and nighttime blood pressure values and was evident also in the last hours of the recording, the trough-to-peak ratio being 0.6 for systolic and 0.7 for diastolic blood pressure. Thus, trandolapril at a dose of 2 mg once daily is an effective long-lasting antihypertensive drug.

Ambulatory blood pressure monitoring in the evaluation of antihypertensive treatment: additional information from a large data base.

Aims of our study were i) to compare in a large number of hypertensive subjects the relative effect of antihypertensive treatment on clinic (C) blood pressure (BP) and various ambulatory (A) BP components, and ii) to determine whether antihypertensive treatment affects BP variability. In 266 mild essential hypertensive outpatients (age: 18-78 years) CBP (trough measurements) and ABP (Spacelabs 90202 or 90207) were measured after 3 to 4 weeks of wash-out and after 4 to 8 weeks of treatment with an ACE-inhibitor (n = 135) or a calcium-antagonist (n = 131). ABP recordings were analyzed to obtain average 24 h, day-time (6 a.m. to midnight) and night-time (midnight to 6 a.m.) systolic and diastolic BP values and standard deviations (BP variabilities). Treatment reduced both CBP and ABP. Treatment-induced changes in CBP showed a poor correlation with those in 24h, day- and night-time BP (r never > 0.23) and the correlation was poor also when trough ABP (mean of last 2 h) was considered. Twenty-four hour, day- and night-time BP were similarly reduced by treatment with a direct relationship between the initial BP values and the subsequent BP falls. BP standard deviations were also reduced by treatment in relation to the pretreatment values but the overall reduction was small, limited to the day-time and proportional or less than proportional to the reduction in mean values, with no changes or an increase in variation coefficients. The effects of ACE-inhibitor and calcium-antagonist treatments were superimposable. Our results from a large data base show that antihypertensive treatment effectively reduces all ABP components. The reduction cannot be predicted by the concomitant fall in CBP but it relates to the initial ABP values. Treatment has a limited effect on BP variability, this being the case both for ACE-inhibitors and calcium-antagonists.

Lack of placebo effect on ambulatory blood pressure.

Several studies have reported that, at variance with clinic blood pressure, ambulatory blood pressure is not reduced by treatment with placebo. However, this evidence has usually been obtained in small groups of subjects and no data are available from a larger sample of patients. To address this issue we have analyzed data from 116 outpatients involved in placebo-controlled studies on antihypertensive treatment. The patients were studied before and at the end of a 6- to 8-week period of placebo. In all patients, blood pressure was measured by sphygmomanometry and over the 24 h by automatic ambulatory monitoring. Administration of placebo was accompanied by a significant reduction in systolic and diastolic clinic blood pressure (-5.3 +/- 1.1 and -4.4 +/- 0.6 mm Hg, respectively; P < .01), but not in 24-h, daytime and nighttime blood pressure. Hourly systolic and diastolic blood pressure profiles were virtually superimposable in the two different periods, except for the first 4 h, in which systolic blood pressure was slightly but significantly lower during than before placebo (149.5 +/- 1.2 v 146.4 +/- 1.2 mm Hg; P < .05). These results provide a large database indicating that 24-h average blood pressure is not reduced by placebo, thus it is not necessary to include a placebo control group in antihypertensive drug studies in which ambulatory blood pressure monitoring is employed. A small placebo effect occurs, however, in the first hours of ambulatory monitoring. This may lead to a slight overestimation of the peak blood pressure effect of a drug and an underestimation of its trough-to-peak ratio if placebo correction of the data is not made or if the first part of ambulatory blood pressure monitoring is not excluded from data analysis.

Ambulatory blood pressure monitoring in the evaluation of antihypertensive drugs.

CLINIC VERSUS AMBULATORY BLOOD PRESSURE MEASUREMENT: Clinic blood pressure measurements do not give the best estimate of the efficacy of antihypertensive drugs because (1) they provide readings for one time-point only, (2) they are subject to a 'white-coat' effect and also show a significant placebo effect and (3) they are poorly reproducible. Ambulatory blood pressure monitoring overcomes these problems and offers the possibility of obtaining reliable, reproducible and detailed information on the time-course and magnitude of the effect of antihypertensive treatment on blood pressure over 24 h. MEAN 24-H VERSUS MEAN HOURLY AMBULATORY BLOOD PRESSURE VALUES: Compared with mean 24-h values, reproducibility is poorer for mean hourly ambulatory values, which show greater variability when tested under different conditions. Thus, caution must be exercised when the effects of antihypertensive drugs on hourly blood pressure profiles are analysed and the trough:peak ratio is calculated. FURTHER PROBLEMS WITH AMBULATORY MONITORING: There are further reasons for caution: (1) ambulatory blood pressure readings can be inaccurate, (2) there is only preliminary information on normal reference values and (3) there have been no longitudinal studies demonstrating the prognostic value of ambulatory blood pressure monitoring, which introduces uncertainty into attempts to evaluate the optimal effect of antihypertensive treatment by this method. CONCLUSIONS: These limitations do not detract from the use of ambulatory blood pressure monitoring in drug studies, but they do suggest that this measurement technique should not be used routinely for assessing antihypertensive treatment in clinical practice.

Clinical use of ambulatory blood pressure monitoring: a critical appraisal.

Traditional sphygmomanometric techniques are heavily affected by the 'white-coat' effect and cannot be used to assess blood pressure variability over the 24h period. These limitations can be overcome in part using ambulatory monitoring, which (1) quantifies both the mean and the variability of blood pressure over 24h, including blood pressure fluctuations between day and night, (2) does not trigger any alerting reaction in the patient, (3) provides reproducible 24h blood pressure means and (4) allows the action of antihypertensive drugs to be assessed over 24h without interference from a placebo effect. Moreover, ambulatory blood pressure values are more closely related to the end-organ damage associated with hypertension than are isolated clinic readings. However, the limited accuracy of ambulatory monitoring in ambulant individuals, the lack of normal reference values for 24h blood pressure and the need for a longitudinal demonstration of the prognostic value of the technique do not permit the recommendation of its widespread use in clinical hypertension. Although the clinical use of ambulatory monitoring should be restricted to selected cases, there is general agreement on its usefulness in clinical pharmacology trials and in studies aimed at assessing cardiovascular regulation through the analysis of 24h blood pressure and heart rate fluctuations.

Blood pressure variability: clinical implications and effects of antihypertensive treatment.

HYPOTHESIS ON RELATIONSHIP BETWEEN BLOOD PRESSURE VARIABILITY AND END-ORGAN DAMAGE: Several studies have shown that the cardiovascular complications of hypertension are more closely related to ambulatory 24-h or daytime average blood pressure than to office readings. A few studies have also provided evidence that in hypertensive patients, not only average ambulatory blood pressure but also the degree of blood pressure variability is significantly and independently related to the end-organ damage associated with hypertension. LIMITATIONS OF PREVIOUS STUDIES: A common limitation of previous studies is that they were based on cross-sectional or retrospective observations, so that the correlative evidence they provide does not allow the relationship between blood pressure variability and end-organ damage to be interpreted causally. EVIDENCE FROM RECENT STUDIES: Recent evidence from follow-up observations has strongly supported the hypothesis that blood pressure variability is prognostically important in hypertensive patients. These findings suggest that optimal antihypertensive treatment should aim not only to reduce mean blood pressure levels, but also to reduce the degree of blood pressure fluctuation. EFFECTS OF ANTIHYPERTENSIVE DRUGS: Unfortunately, while most new antihypertensive drugs seem to be effective in reducing 24-h mean blood pressure levels, they are frequently unable to reduce 24-h blood pressure variability, which is often increased during treatment when expressed in normalized units. The development of drugs that guarantee a constant and uniform reduction in blood pressure over 24 h may, in principle, offer a further advantage by preventing the increase in 24-h blood pressure fluctuations that may follow the administration of short-acting antihypertensive agents. TROUGH: PEAK MEASUREMENTS OF BLOOD PRESSURE: The trough: peak ratio, proposed as an arithmetic indicator of the duration of the antihypertensive effect of a drug, may be a useful measure of the occurrence of a smooth reduction in blood pressure over 24 h. The possibility of obtaining an additional reduction in cardiovascular risk for hypertensive patients by minimizing the net trough: peak effect of antihypertensive drugs is thus an important issue for future studies.

Twenty-four-hour ambulatory blood pressure monitoring and antihypertensive treatment: focus on ACE inhibitors.

The use of ambulatory blood pressure monitoring in clinical studies offers some advantages in comparison to the clinic blood pressure measurement. In fact, this approach does not induce any alerting reaction and provides 24-h blood pressure values that are more reproducible and not affected by the placebo effect. This allows a better evaluation of blood pressure under antihypertensive treatment and an optimization of the number of patients to be studied in pharmacologic trials. In a recent double-blind, parallel-group study, ambulatory blood pressure monitoring was used to investigate the antihypertensive efficacy of a new angiotensin-converting enzyme inhibitor, trandolapril, in 62 mild and moderate hypertensive patients. After a washout period, patients received trandolapril, 2 mg o.d., or placebo for 6 weeks, followed by a second washout period. Clinic and 24-h blood pressures were assessed at the end of each period. In comparing the pre- and post-treatment period, trandolapril significantly reduced clinic and 24-h systolic and diastolic blood pressures. The fall was evident throughout the 24 h and was statistically significant also in the last 4 h of blood pressure monitoring. The placebo group did not show any significant blood pressure change. Thus, trandolapril, 2 mg once daily, is effective in reducing blood pressure. Its efficacy over 24 h is better documented by 24-h blood pressure monitoring than by isolated clinic blood pressure measurement.

Ambulatory blood pressure monitoring in the diagnosis of hypertension and evaluation of antihypertensive drug efficacy.

Ambulatory blood pressure monitoring is invaluable in the assessment of the efficacy of antihypertensive drug treatment because it allows the reduction of blood pressure to be confirmed within the context of daily life. It also allows the determination of whether treatment produces an even blood pressure reduction over the 24-hour period or whether it is characterized by an uneven profile, for example, a precipitous fall early after administration of the drug and a later return towards elevated blood pressure values. A lack of information on prognostic and normal values does not permit quantification of the optimal blood pressure reduction to be achieved throughout the monitoring period. It is agreed, however, that the decrease should take into consideration both the elevated daytime and the reduced night-time blood pressures, and that peak blood pressure values associated with physical and emotional activities as well as the overall variability of blood pressure should also be reduced. Finally, ambulatory blood pressure monitoring is virtually devoid of the placebo effect, and the 24-hour average blood pressure data derived by this method are more reproducible than isolated blood pressure values taken by sphygmomanometry. This offers distinct advantages for studies designed to evaluate the antihypertensive effect of new drugs.

Ambulatory blood pressure monitoring in elderly hypertensive patients.

Ambulatory blood pressure monitoring (ABPM) has been shown to provide a reliable estimation of hourly blood pressure values over the 24 hours. Favourable features of this technique are the lack of alerting reaction to automatic blood pressure readings, at variance from what usually occurs when blood pressure is measured in the doctor's office, and the ability of ABPM to provide information on the 24 hour blood pressure profile without interfering with the physiological nocturnal hypotension. Although automatic blood pressure readings obtained in free-moving subjects are not always accurate, ABPM has been shown to represent a useful approach to evaluate the efficacy of antihypertensive drugs, as it allows to compare the 24 hour blood pressure profile obtained before and during treatment. Its feasibility to this aim is emphasized by the reproducibility of 24 hour ambulatory blood pressure profiles, which do not show any placebo effect. ABPM has been also employed to investigate 24 hour blood pressure fluctuations and to monitor the antihypertensive treatment in elderly hypertensives, in whom the evaluation of the actual time-course of the drug-induced blood pressure reduction over the day and night represents a crucial problem.

Ambulatory blood pressure monitoring and antihypertensive treatment.

Ambulatory blood pressure monitoring is becoming increasingly popular among clinicians and investigators because of its potential to overcome the well-known limitations inherent to conventional blood pressure measurement. This paper will focus on the use of this approach in the evaluation of antihypertensive treatment. It will be argued that due to lack of prognostic validity and high cost, ABPM should not be employed routinely in treating hypertensives. It should always be employed, however, for the evaluation of the efficacy of new hypertensive drugs for which its superiority over sphygmomanometry is indisputable. This is exemplified by the results of a recent multicenter, double-blind, parallel group study on the effect of verapamil SR 240 mg, enalapril 20 mg and nitrendipine 20 mg and placebo, all administered once a day for eight weeks. Compared to placebo, all drugs reduced 24-hour mean blood pressure sufficiently. The reduction was evident throughout the daytime but nighttime blood pressure was more effectively lowered by verapamil and enalapril than by nitrendipine, documenting a difference that was not visible by using conventional measurements.

Clinical value of blood pressure measurements: focus on ambulatory blood pressures.

Because clinic blood pressure values are compromised by 2 major limitations--the alerting reaction to clinic measurements and the spontaneous blood pressure variability--they have only a limited correlation with average 24-hour blood pressure values. Whether the latter should be employed routinely in substitution for, or in addition to, traditional blood pressure measurements has not yet been determined, however. To date, average 24-hour blood pressure values have been shown to correlate more closely than clinic blood pressure values with the organ damage of hypertension. A correlation with organ damage has been shown also for a number of blood pressure values within the 24 hours. Nevertheless, the clinical importance of 24-hour blood pressure and blood pressure variability has never been confirmed by prospective controlled studies. This information needs to be obtained before this approach is routinely employed in the clinical practice.

Changes in 24 hour blood pressure and in cardiac and vascular structure in normotensive subjects with parental hypertension.

Subjects with family history of hypertension represent a suitable model to investigate the mechanisms responsible for early cardiovascular structural and functional changes occurring in essential hypertension. In our study we have addressed the factors involved in determining the mild elevation in office blood pressure frequently observed in normotensive subjects with hypertensive parents. In 15 normotensive subjects with both parents hypertensive (FH++) and in 15 normotensive subjects with one parent hypertensive (FH(+)-) we found no evidence of a hyperreactivity to stress as compared to the responses of 15 normotensive subjects with no parental hypertension (FH--). On the contrary FH++ subjects were characterized by a significant although mild increase in their blood pressure values recorded either at rest and in ambulatory conditions over the 24 hours, including night sleep. FH++ and FH(+)- subjects also showed a greater left ventricular mass thickness and a greater minimal forearm vascular resistance than FH-- subjects. Thus, the elevation in blood pressure found in the pre-hypertensive stage in subjects with positive family history for hypertension does not reflect a hyperreactivity to the stress associated with physician's visit but indicates an early and persistent blood pressure elevation. This blood pressure elevation is accompanied by early cardiovascular structural changes which may indicate that these subjects are exposed to a higher risk even before developing overt hypertension.

Ambulatory blood pressure monitoring.

This paper reviews the evidence that, in patients with hypertension, end-organ damage correlates more closely with blood pressure values obtained by ambulatory blood pressure monitoring than with those obtained by conventional sphygmomanometry. However, ambulatory blood pressure monitoring is not suitable for routine use in the clinical setting because of a lack of standard reference values and data regarding the prognostic significance of this method. Ambulatory blood pressure values are reproducible and this method avoids the so-called placebo effect; thus, this method is useful in clinical studies investigating the efficacy and duration of action of antihypertensive drugs. Data from 1 study in which hypertensive patients were treated with slow release verapamil 240 mg, enalapril 20 mg, nitrendipine 20 mg and placebo, given once daily for 8 weeks according to a double-blind parallel group design, showed that mean 24-hour ambulatory blood pressure was reduced by all 3 drugs compared with placebo. Verapamil and enalapril showed similar antihypertensive efficacy and both drugs reduced night-time blood pressure more effectively than nitrendipine.

Prognostic value of ambulatory blood pressure monitoring.

Ambulatory blood pressure monitoring has both advantages and disadvantages in clinical practice. The structural and functional organ abnormalities associated with hypertension are more closely correlated to 24-h blood pressure mean values than to clinic or other conventional sphygmomanometric blood pressures. Furthermore, an additional relationship can be seen between the incidence and severity of these abnormalities and the magnitude of day and night blood pressure changes or 24-h blood pressure variability. However, controlled prospective studies are still required to demonstrate that ambulatory blood pressure data are superior or add to the prognostic value of clinic blood pressure. Moreover, ambulatory blood pressure normalcy has not yet been properly defined. This suggests caution in the practical use of this technique, which should be limited to special groups of subjects (those with a possible alerting reaction to conventional blood pressure assessments, in whom home blood pressure measurements are unreliable) and should only be used by clinicians with expertise in the field.

Methodological problems in evaluation of cardiovascular effects of stress in humans.

Cardiovascular effects of stress in humans are often assessed by application of physical or emotional stimuli in a laboratory environment. Although this method provides important information, these procedures have several limitations. First, blood pressure and heart rate responses to laboratory stressors are characterized by a limited within-subject reproducibility. Second, there is poor correlation between blood pressure and heart rate responses to different stressors, which implies that individual reaction to stress may be estimated differently according to the test used. Finally, these responses bear only a limited relation to 24-hour or daytime blood pressure variability, that is, they reflect to only a limited extent the tendency of blood pressure to vary during daily activities. If assessed by techniques that allow blood pressure to be continuously recorded for 24 hours in ambulatory subjects, blood pressure variability represents a possible approach to observation of cardiovascular reactivity away from an artificial laboratory environment. However, whether blood pressure variability should be expressed as a percentage or in absolute values is controversial. Furthermore, although naturally occurring stress may markedly increase blood pressure, 24-hour blood pressure variations also depend on factors that are not related to emotional stimuli. Thus, the study of cardiovascular responses to stress in humans encounters several problems, regardless of the method used.