Frovatriptan vs. other triptans for the acute treatment of oral contraceptive-induced menstrual migraine: pooled analysis of three double-blind, randomized, crossover, multicenter studies.

Oral contraceptive-induced menstrual migraine (OCMM) is a particularly severe form of migraine triggered by the cyclic hormone withdrawal. To review the efficacy of frovatriptan vs. other triptans, in the acute treatment of OCMM through a pooled analysis of three individual randomized Italian studies. With or without aura migraineurs were randomized to frovatriptan 2.5 mg or rizatriptan 10 mg (study 1), frovatriptan 2.5 mg or zolmitriptan 2.5 mg (study 2), frovatriptan 2.5 mg or almotriptan 12.5 mg (study 3). All studies had a multicenter, randomized, double-blind, crossover design. After treating 1-3 episodes of migraine in 3 months with the first treatment, patients switched to the other treatment for the next 3 months. In this analysis, the subset of 35 of the 280 women of the intention-to-treat population taking combined oral contraceptives and experiencing a migraine attack during the withdrawal phase, were analyzed. The proportion of pain free and pain relief at 2 h were 25 and 51 % with frovatriptan and 28 and 48 % with comparators (p = NS). At 24 h, 71 and 83 % of frovatriptan-treated patients and 60 and 76 % of comparator-treated patients were pain free (p < 0.05 between treatments) and had pain relief (p = NS), respectively. Relapse at 24 and 48 h was significantly (p < 0.05) lower with frovatriptan (17 and 21 %) than with the comparators (27 and 31 %). Our results suggest that, due to its sustained antimigraine effect, frovatriptan may be particularly suitable for the management of OCMM than other triptans.

Efficacy of frovatriptan and other triptans in the treatment of acute migraine of hypertensive and normotensive subjects: a review of randomized studies.

Migraine might be associated with high blood pressure (BP), which can cause more severe and more difficult to treat forms of headache. To evaluate the efficacy of frovatriptan and other triptans in the acute treatment of migraine, in patients classified according to a history of arterial hypertension, enrolled in three randomized, double-blind, crossover, Italian studies. Migraineurs with or without aura were randomized to frovatriptan 2.5 mg or rizatriptan 10 mg (study 1), frovatriptan 2.5 mg or zolmitriptan 2.5 mg (study 2), frovatriptan 2.5 mg or almotriptan 12.5 mg (study 3). After treating up to three episodes of migraine in 3 months with the first treatment, patients switched to the alternate treatment for the next 3 months. The present analysis assessed triptan efficacy in 60 subjects with a history of treated or untreated essential arterial hypertension (HT) and in 286 normotensive (NT) subjects. During the study, migraine attacks with aura were significantly more prevalent in HT subjects (21 vs. 13 % NT, p < 0.001). The proportion of pain free at 2 h did not significantly differ between HTs and NTs for either frovatriptan (25 vs. 26 %) or the comparators (33 vs. 32 %). Pain relief was achieved in significantly (p < 0.05) fewer episodes in HT subjects for both frovatriptan (41 vs. 52 % NT) and the comparators (48 vs. 58 %). Relapses at 48 h were similarly low in HTs and NTs with frovatriptan (29 vs. 31 %), while they were significantly (p < 0.05) larger in HTs (62 %) than in NTs (44 %) with comparators. No BP or heart rate increment was observed during the study in HT subjects. No difference in tolerability was reported between HTs and NTs. In conclusion, HT individuals tend to be less responsive than NT migraineurs to triptan therapy. However, frovatriptan, in contrast to other triptans, seems to have a sustained antimigraine effect in both HT and NT patients.

Restless legs syndrome is not associated with migraine with aura: a clinical study.

Based on recent data about the association between restless legs syndrome (RLS) and migraine, we performed an observational study on the occurrence of RLS in patients affected by "pure" migraine with aura (pMA). We recruited 63 patients (33 females and 30 males) affected by MA without other types of primary headache among all patients referred in five Italian headache centers in a 1-year period. The prevalence of RLS in pMA patients (9.5%) is similar to that observed in Italian headache-free subjects (8.3%). No significant differences were found between pMA patients with and without RLS about clinical features of MA attacks and systemic and psychiatric diseases were investigated. Moreover, no association appeared between RLS and familial cases of MA. Differently from migraine without aura, our data do not confirm the existence of an association between RLS and MA, not even when a genetic factor is involved.

Self-monitoring of Blood Pressure in Patients With Hypertension-Related Multi-morbidity: Systematic Review and Individual Patient Data Meta-analysis.

BACKGROUND: Studies have shown that self-monitoring of blood pressure (BP) is effective when combined with co-interventions, but its efficacy varies in the presence of some co-morbidities. This study examined whether self-monitoring can reduce clinic BP in patients with hypertension-related co-morbidity. METHODS: A systematic review was conducted of articles published in Medline, Embase, and the Cochrane Library up to January 2018. Randomized controlled trials of self-monitoring of BP were selected and individual patient data (IPD) were requested. Contributing studies were prospectively categorized by whether they examined a low/high-intensity co-intervention. Change in BP and likelihood of uncontrolled BP at 12 months were examined according to number and type of hypertension-related co-morbidity in a one-stage IPD meta-analysis. RESULTS: A total of 22 trials were eligible, 16 of which were able to provide IPD for the primary outcome, including 6,522 (89%) participants with follow-up data. Self-monitoring was associated with reduced clinic systolic BP compared to usual care at 12-month follow-up, regardless of the number of hypertension-related co-morbidities (-3.12 mm Hg, [95% confidence intervals -4.78, -1.46 mm Hg]; P value for interaction with number of morbidities = 0.260). Intense interventions were more effective than low-intensity interventions in patients with obesity (P < 0.001 for all outcomes), and possibly stroke (P < 0.004 for BP control outcome only), but this effect was not observed in patients with coronary heart disease, diabetes, or chronic kidney disease. CONCLUSIONS: Self-monitoring lowers BP regardless of the number of hypertension-related co-morbidities, but may only be effective in conditions such obesity or stroke when combined with high-intensity co-interventions.

Impairment of the arterial baroreflex during symptomatic and silent myocardial ischemia in humans.

OBJECTIVES: The aim of this study was to assess whether transient episodes of symptomatic or silent myocardial ischemia after baroreceptor modulation of heart rate. BACKGROUND: Animal and human studies have shown that myocardial infarction is accompanied by an impairment of the baroreceptor influences on the sinus node. However, whether this also occurs during transient myocardial ischemia has never been documented. METHODS: In 12 patients undergoing coronary angiography, systolic blood pressure (intraarterial catheter) was reduced by an intravenous bolus of nitroglycerin during a spontaneous episode of transient chest pain and myocardial ischemia (ST segment depression on the electrocardiogram) and 30 min after recovery. The slope of the linear regression between the decrease in systolic blood pressure and the RR interval shortening was taken as the measure of baroreflex sensitivity. RESULTS: During ischemia, baroreflex sensitivity was 1.3 +/- 0.3 ms/mm Hg (mean +/- SEM), whereas after recovery it was markedly and significantly greater (2.6 +/- 0.5 ms/mm Hg, p < 0.01). Similar results were obtained in eight other patients who experienced a silent ischemic episode either spontaneously or during coronary angioplasty. The reduction in baroreflex sensitivity was similarly pronounced during inferior (10 patients) and anterior (10 patients) ischemia, and its magnitude showed little or no relation to the ischemia-dependent changes in blood pressure and heart rate. CONCLUSIONS: Transient myocardial ischemia is associated with marked baroreflex impairment. The impairment occurs even during symptomless ischemic episodes and is therefore not related to pain or to other nonspecific influences on the baroreflex.

Evaluation of noninvasive blood pressure monitoring devices Spacelabs 90202 and 90207 versus resting and ambulatory 24-hour intra-arterial blood pressure.

This study evaluated the accuracy of blood pressure values provided by the Spacelabs 90202 and 90207 devices in comparison with intra-arterial recording in 19 subjects at rest and in nine subjects in ambulatory conditions (Oxford method). At rest Spacelabs monitors reflected intra-arterial systolic blood pressure values very closely but overestimated to a considerable extent intra-arterial diastolic blood pressure (Spacelabs-intra-arterial differences, -0.8 +/- 9.2, NS, and 9.1 +/- 8.8 mm Hg, p less than 0.01, for systolic and diastolic blood pressures, respectively). In ambulatory conditions Spacelabs-intra-arterial average differences in 24-hour values were +0.4 +/- 5.1 mm Hg for systolic blood pressure (NS) and +14.0 +/- 2.9 mm Hg for diastolic blood pressure (p less than 0.01) when group data were considered. The performance of both Spacelabs devices was worse when assessed in individual subjects or for each hourly interval. In spite of these differences between noninvasive and intra-arterial absolute blood pressure values, however, Spacelabs 90202 and 90207 monitors were able to faithfully reflect directional hour-to-hour changes in intra-arterial blood pressure (chi 2 = 18.2 and chi 2 = 23.1 for systolic and diastolic blood pressures, respectively, p less than 0.01). No differences were found between the performance of the two Spacelabs devices. Thus, although the absolute accuracy of blood pressure values provided by these monitors in ambulatory subjects is still limited, they seem to be suitable for studies aimed at assessing 24-hour blood pressure profiles quantitatively as well as qualitatively.

Difference between clinic and daytime blood pressure is not a measure of the white coat effect.

The purpose of the present study was to evaluate whether the difference between blood pressure measured in the clinic or physician's office and the average daytime blood pressure accurately reflects the blood pressure response of the patient to the physician ("white coat effect" or "white coat hypertension"). We studied 28 hypertensive outpatients (mean age, 41.8+/-11.2 years; age range, 21 to 64 years) of 35 consecutive patients attending our hypertension clinic, in whom (1) continuous noninvasive finger blood pressure was recorded before and during the visit, (2) blood pressure was measured according to the Riva-Rocci-Korotkoff method (mercury sphygmomanometer) with the patient in the supine position, and (3) daytime ambulatory blood pressure was monitored with a SpaceLabs 90207 device. The peak blood pressure increase recorded directly during the visit was compared with the difference between clinic and daytime average ambulatory blood pressures. Compared with previsit values, peak increases in finger systolic and diastolic blood pressures during the visit to the clinic were 38.2+/-3.1 and 20.7+/-1.6 mm Hg, respectively (mean+/-SEM, P<.01 for both). Daytime average systolic and diastolic blood pressures were 135.5+/-2.5 and 89.2+/-1.9 mm Hg, with both lower than the corresponding clinic blood pressure values (146.6+/-3.6 and 94.9+/-2.2 mm Hg, P<.01). These differences, however, were <30% of the peak finger blood pressure increases during the physician's visit, to which these increases showed no relation. Although the visit to the physician's office was associated with tachycardia (9.0+/-1.6 bpm, P<.01), there was no difference between clinic and daytime average heart rates. These data indicate that the clinic-daytime average blood pressure difference does not reflect the alerting reaction and the pressure response elicited by the physician's visit and thus is not a reliable measure of the white coat effect.

Reproducibility and clinical value of the trough-to-peak ratio of the antihypertensive effect: evidence from the sample study.

The objectives of our study were to assess the reproducibility of the trough-to-peak ratio (T/P) and to see whether a high T/P is accompanied by more organ protection or vice versa. The study included 175 (mean+/-SD age, 51+/-9 years) subjects with mild-moderate essential hypertension who had echocardiographic evidence of left ventricular (LV) hypertrophy taken from the SAMPLE study (Study on Ambulatory Monitoring of Blood Pressure and Lisinopril Evaluation), an open-label multicenter study. The study included a 3-week washout pretreatment period, a 12-month treatment period with lisinopril (n=84) or lisinopril plus hydrochlorothiazide (n=91) once daily, and a 4-week placebo follow-up period. Results of 24-hour ambulatory blood pressure monitoring and echocardiographic determination of left ventricular mass index (LVMI) were obtained before and after 3 and 12 months of treatment. T/Ps were computed in each patient by dividing the systolic and diastolic blood pressure changes at trough (changes in the last 2 hours of the monitoring period) by those at peak (average of the 2 adjacent hours with the maximal blood pressure reduction between the 2nd and 8th hour from drug intake) after 3 and 12 months of treatment. Average 24-hour blood pressure was similarly reduced at 3 and 12 months. Trough blood pressure changes at 3 and 12 months were closely correlated, as were the corresponding peak blood pressure changes. However, the 3- and 12-month T/Ps correlated to a lesser degree (r<0.42). Furthermore, the reduction of LVMI induced by treatment was similarly correlated with the treatment-induced reduction in 24-hour average, trough, and peak blood pressures but not with the T/Ps. This was also evident when the contribution to LV hypertrophy regression by 24-hour blood pressure changes and T/Ps was assessed in a multivariate regression analysis. In patients with a T/P >/=0.5 or <0.5, the regression of LVMI was similar. In conclusion, peak and trough blood pressure changes are reproducible and predict the regression of LVMI induced by treatment as well as average 24-hour blood pressure. T/Ps are less reproducible, and their value does not predict regression of organ damage by antihypertensive treatment.

Spectral and sequence analysis of finger blood pressure variability. Comparison with analysis of intra-arterial recordings.

The aim of our study was to assess whether the Finapres device is able to accurately monitor not only average blood pressure values but also blood pressure variability. To examine this issue, we analyzed 30-minute recordings of finger and intra-arterial pressure simultaneously obtained at rest in 14 patients. We compared systolic blood pressure, diastolic blood pressure, mean arterial pressure, pulse interval (the reciprocal of heart rate), overall variability (standard deviation), and specific time-domain and frequency-domain components. Systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse interval spectral powers were computed by fast Fourier transform over three frequency bands: low frequency (0.025 to 0.07 Hz), midfrequency (0.07 to 0.14 Hz), and high frequency (0.14 to 0.35 Hz). The coherence, ie, the degree of association between blood pressure and pulse interval powers obtained by the two techniques, was also assessed. Standard deviations of diastolic blood pressure, mean arterial pressure, and pulse interval were similar when assessed from the two recordings, whereas standard deviation of systolic blood pressure was overestimated by analysis of finger pressure recordings. All powers of diastolic blood pressure and mean arterial pressure and high-frequency powers of systolic blood pressure estimated from analysis of finger blood pressure tracings were superimposable to those obtained by analyzing invasive recordings. Low-frequency and midfrequency powers of intra-arterial systolic blood pressure were significantly overestimated by the analysis of finger blood pressure tracings (+13.7 +/- 4.4 mm Hg2, P < .01, and +2.3 +/- 0.9 mm Hg2, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Sequential spectral analysis of 24-hour blood pressure and pulse interval in humans.

Blood pressure and pulse interval are characterized not only by erratic variations but also by rhythmic fluctuations at low-, mid-, and high-frequency (0.025-0.07, 0.07-0.14, and 0.14-0.35 Hz, respectively). However, information on these phenomena has largely been derived from analysis of short-term recordings taken in standardized laboratory conditions. In seven normotensive and 10 untreated mild essential hypertensive subjects, power spectrum analysis was performed on the intra-arterial blood pressure and pulse interval signal collected over a 24-hour period using the fast Fourier transform algorithm and splitting the recording into contiguous segments of 256 beats. About 70% of the segments were suitable for the analysis; the segments excluded for a nonstationary signal amounted to only 30%. All powers were characterized by a high segment-to-segment variability, but in each subject the mid- and high-frequency powers of diastolic blood pressure and the mid-frequency power of systolic blood pressure were markedly reduced during the night as compared with the daytime period, whereas the opposite occurred for the low- and high-frequency powers of the pulse interval. Over the 24-hour period, mid- and high-frequency powers of blood pressure were positively correlated to each other, but both accounted for less than 25% of the 24-hour blood pressure variance. No difference between mean normalized power values of normotensive and hypertensive subjects was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Estimation of blood pressure variability from 24-hour ambulatory finger blood pressure.

Portapres is a noninvasive, beat-to-beat finger blood pressure (BP) monitor that has been shown to accurately estimate 24-hour intra-arterial BP at normal and high BPs. However, no information is available on the ability of this device to accurately track ambulatory BP variability. In 20 ambulatory normotensive and hypertensive subjects, we measured 24-hour BP by Portapres and through a brachial artery catheter. BP and pulse interval variabilities were quantified by (1) the SDs of the mean values (overall variability) and (2) spectral power, computed either by fast Fourier transform and autoregressive modeling of segments of 120-second duration for spectral components from 0.025 to 0.50 Hz or in a very low frequency range (between 0.00003 and 0.01 Hz) by broadband spectral analysis. The 24-hour SD of systolic BP obtained from Portapres (24+/-2 mm Hg) was greater than that obtained intra-arterially (17+/-1 mm Hg, P<0.01), but the overestimation was less evident for diastolic (3+/-1 mm Hg, P<0.01) and mean (3+/-1 mm Hg, P<0.01) BP. The BP spectral power <0.15 Hz was also overestimated by Portapres more for systolic than for diastolic and mean BPs; similar findings were obtained by the fast Fourier transform, the autoregressive approach, and focusing on the broadband spectral analysis. BP spectral power >0.15 Hz obtained by the Portapres was similar during the day but lower during the night when compared with those obtained by intra-arterial recordings (P<0.01). No differences were observed between Portapres and intra-arterial recordings for any estimation of pulse interval variabilities. The overestimation of BP variability by Portapres remained constant over virtually the entire 24-hour recording period. Thus, although clinical studies are still needed to demonstrate the clinical relevance of finger BP variability, our study shows that Portapres can be used with little error to estimate 24-hour BP variabilities if diastolic and mean BPs are used. For systolic BP, the greater error can be minimized by using correction factors.

Antihypertensive efficacy of lercanidipine at 2.5, 5 and 10 mg in mild to moderate essential hypertensives assessed by clinic and ambulatory blood pressure measurements. Multicenter Study Investigators.

OBJECTIVE: To evaluate the antihypertensive effect of lercanidipine once a day at three different doses (2.5, 5 and 10 mg) by clinic and ambulatory blood pressure. METHODS: After 3 weeks of a placebo run-in, 243 mild to moderate essential hypertensives (mean+/-SD age 51+/-8 years) were randomly allocated to lercanidipine at 2.5, 5 or 10 mg or a placebo for 4 weeks, in a double-blind parallel-group design. At the end of each period, supine clinic blood pressure (standard sphygmomanometry) and 24 h ambulatory blood pressure (Spacelabs 90207) were measured. The duration and homogeneity of the antihypertensive effect of the active drug compared with placebo over 24 h was evaluated by calculating the smoothness index, the ratio of the mean of the 24 hourly blood pressure changes to the corresponding SD. The higher the smoothness index, the greater and the smoother is the antihypertensive effect of a drug over the 24 h. RESULTS: In 211 patients with valid clinic blood pressure data at the end of treatment, larger systolic/diastolic blood pressure reductions were found in the 5 mg (10+/-12/8+/-6 mmHg; P< 0.05 versus placebo, diastolic blood pressure only) and the 10 mg (12+/-11/9+/-7 mmHg; P < 0.05 versus placebo, both pressures) lercanidipine groups than in the placebo (5+/-11/4+/-8 mmHg) and 2.5 mg lercanidipine (7+/-12/6 +/-7 mmHg) groups. In 105 patients with complete 24 h ambulatory blood pressure recordings, there were significantly (P< 0.05 versus placebo) larger reductions in the 10 mg (9+/-7/7+/-5 mmHg) than the 2.5 mg (1+/-10/1+/-6 mmHg) and placebo (2+/-6/1+/-4 mmHg) groups. The reduction in 24 h blood pressure with 5 mg lercanidipine (6+/-7/4+/-5 mmHg) was significantly greater compared with placebo for diastolic pressure only, and when hourly average blood pressure changes were considered, this reduction did not extend to the final hours of the dosing interval. No significant changes in the clinic or 24 h heart rate were induced by placebo or lercanidipine. The smoothness index was significantly (P< 0.05) lower for 2.5 mg lercanidipine and placebo (0.2+/-0.5 and 0.3+/-0.7 for systolic and 0.1+/-0.4 and 0.2+/-0.7 for diastolic blood pressure) than for the 5 and 10 mg doses (0.7+/-1 and 1+/-0.7 for systolic and 0.7+/-1 and 1+/-0.9 for diastolic blood pressure). CONCLUSIONS: At a dose of 10 mg, lercanidipine had a significant and durable antihypertensive effect over 24 h, but at 5 mg, the effect was less consistent and did not last 24 h. There was no clinically relevant reduction in clinic or ambulatory blood pressure with 2.5 mg lercanidipine, and the effect was superimposable on that of placebo.

Difference between office and ambulatory blood pressure and response to antihypertensive treatment.

OBJECTIVE: To investigate whether a clinic-ambulatory blood pressure difference persists with time under active drug treatment or placebo and to determine whether and how it interferes with the evaluation of the efficacy of antihypertensive treatment. DESIGN AND METHODS: In 382 mild or moderate essential hypertensive patients (mean age +/- SD 51.5 +/- 9.2 years) clinic and ambulatory (SpaceLabs 90207 device) blood pressures were measured twice, under baseline conditions and after 4-8 weeks of antihypertensive treatment by calcium antagonists or angiotensin converting enzyme inhibitors (n = 266) or of placebo administration (n = 116). In each patient the difference between clinic and daytime average blood pressure was taken as a surrogate measure of the magnitude of the 'white-coat effect', separately for systolic and diastolic blood pressures. The changes in this difference induced by treatment and by placebo and the relationship between the blood pressure changes induced by drug treatment and by placebo and the magnitude of the difference before and during treatment or placebo, respectively, were computed. RESULTS: Before drug treatment, the difference was 16.6 +/- 13.6 and 10.1 +/- 7.9 mmHg for systolic and diastolic blood pressures, respectively. During treatment the corresponding values were 11.9 +/- 14.2 and 6.8 +/- 9.2 mmHg; both of the reductions were statistically significant. Both for systolic and for diastolic blood pressure, the reduction in clinic blood pressure caused by treatment was directly related to the clinic-ambulatory difference before treatment, but inversely related to the magnitude of that difference persisting during treatment. The clinic-ambulatory blood pressure difference observed before placebo was attenuated during placebo, the magnitude of the attenuation being similar to that found under drug treatment. No significant difference between clinic and daytime average heart rate was ever observed before and during active treatment or placebo. CONCLUSIONS: A considerable clinic-ambulatory blood pressure difference persists during several weeks of antihypertensive treatment, but its magnitude is significantly attenuated. This leads to an overestimation of the effectiveness of antihypertensive treatment when this is assessed by clinic blood pressure measurements only. This overestimation is greater in subjects with an initially greater difference because in these subjects the subsequent attenuation is greater. Because similar phenomena are observed with placebo, the attenuation in the difference during drug treatment is likely to reflect merely habituation to clinic blood pressure measurements with time.

Calculation of trough:peak ratio of antihypertensive treatment from ambulatory blood pressure: methodological aspects.

OBJECTIVE: To address several methodological questions related to calculation of trough:peak ratio from 24 h ambulatory blood pressure (BP) recordings. METHODS: Data from patients with mild essential hypertension who were included in parallel group (n = 280) or cross-over studies (n = 39) were pooled. 24 h ambulatory BP recordings were available after 2- to 4-week washout from treatment and at the end of a 4- to 8-week period of treatment with calcium antagonists (n = 143), angiotensin converting enzyme inhibitors (n = 103) or placebo (73 patients from parallel group studies and 39 from a cross-over study). Each recording started between 0900 and 1000 h, immediately after the drug or placebo intake during the treatment phase. BP was measured at 15 min intervals during the day and at 15-20 min intervals during the night. Peak changes were calculated from systolic BP and diastolic BP 2-8 h after drug intake, and trough changes from readings taken during the last 4 h of the 24 h. RESULTS: Peak changes induced by drug treatment were progressively reduced when data were averaged over 1, 2, 4 and 6 h. BP reproducibility showed a concomitant increase and the best compromise between correct estimate of peak changes and reproducibility was the average of the adjacent 2 h with the maximal BP fall. Peak and trough (average of last 2 h) changes showed a normal distribution, whereas trough:peak ratios showed non-normal distributions, large scatters and many individual values with no pharmacodynamic significance (namely, much above unity and below zero). Selecting responders to treatment reduced the dispersion and made the trough:peak ratio distribution normal. There was no correlation between trough:peak ratios and changes in BP variability (standard deviation of 24 h mean) induced by treatment. Placebo administration caused no trough but a modest peak fall. Peak changes during placebo also showed a wide scatter and a non-normal distribution, which makes correction with respect to average peak placebo data inappropriate in parallel-group studies. However, placebo correction may be performed for each subject in cross-over studies, leading to a reduction in peak changes and an increase in trough:peak ratio values. CONCLUSIONS: When the trough:peak ratio is assessed from ambulatory BP, peak and trough changes should preferably be computed over a 2 h time window. To remove values with no pharmacodynamic significance, the analysis should preferably be conducted only in responders to treatment at peak. Although placebo is accompanied by some peak effect, placebo correction might be appropriate only for individual subjects in cross-over studies.

Effect of placebo on 24-h non-invasive ambulatory blood pressure.

Twenty-four-hour mean ambulatory blood pressure has been shown to be devoid of a placebo effect. However, whether this is the case for different periods within the 24 h has not been established. In 27 essential hypertensive outpatients, blood pressure was measured in the doctor's office and by 24-h ambulatory blood pressure monitoring after a 3-week wash-out period from antihypertensive treatment (Control) and following 4 weeks of placebo administration. Office systolic and diastolic blood pressures were reduced by placebo (-9.6 +/- 2.6 and -3.1 +/- 1.7 mmHg, P less than 0.01, respectively), whereas 24-h mean blood pressure values did not show any significant change. This was not the case for all 24-h subperiods, however, because during the initial 8h, systolic and diastolic blood pressures were slightly (-4.1 +/- 9.2 and -2.5 +/- 6.4 mmHg) but significantly (P less than 0.05) lower during placebo than during control. Similar findings were obtained in 14 additional essential hypertensive patients in whom neither placebo nor any other treatment was employed between the two office and 24-h blood pressure measurements. Thus, placebo treatment is associated with a blood pressure reduction in the initial portion of the ambulatory blood pressure profile, probably because of an attenuation of an initial transient alerting response to the procedure. Although so small as to leave the 24-h blood pressure mean unaffected, this may lead to some overestimation of the antihypertensive effect of treatment during an appreciable portion of the circadian blood pressure tracing.

Persistent blood pressure increase induced by heavy smoking.

OBJECTIVE: To test the hypothesis that heavy smoking is associated with a persistent increase in blood pressure. DESIGN: In 10 normotensive smokers asked to smoke one cigarette every 15 min for 1 h, blood pressure and heart rate were continuously monitored during the smoking period and during the preceding non-smoking hour. In six other normotensive smokers asked to smoke two cigarettes per hour throughout the whole day, blood pressure and heart rate were monitored non-invasively in ambulatory conditions for 8 h (0900-1700 h). Blood pressure monitoring was repeated during a non-smoking day. METHODS: Beat-to-beat blood pressure and heart rate were monitored at rest by means of the Finapres device. Blood pressure signal was sampled at 165 Hz by a computer to calculate hourly data. Ambulatory blood pressure and heart rate were measured once every 10 min. RESULTS: In resting conditions, the first cigarette caused an immediate and marked increase in blood pressure and heart rate, and the peak blood pressure and heart rate achieved were similar for the remaining three cigarettes. In each instance, the hemodynamic effects were so prolonged that throughout the smoking hour, blood pressure and heart rate were persistently higher than during the non-smoking hour. The standard deviations of systolic and diastolic blood pressure and heart rate were also higher during the smoking hour, indicating an increase in blood pressure and heart rate variability. In the six ambulant smokers, daytime blood pressure and heart rate were also persistently higher during smoking than during non-smoking. CONCLUSIONS: Heavy smoking is associated with a persistent rise in blood pressure and also with an increase in blood pressure variability. These effects (which may escape clinic blood pressure measurements performed during non-smoking) may account for some of the smoking-related cardiovascular risk.

Limited reproducibility of hourly blood pressure values obtained by ambulatory blood pressure monitoring: implications for studies on antihypertensive drugs.

OBJECTIVE: To assess the reproducibility of average hourly blood pressure values obtained by 24-h non-invasive ambulatory monitoring. PATIENTS: Fifteen outpatients with essential hypertension. In all subjects antihypertensive treatment was withdrawn for 4 weeks before and during the 4 weeks of the study. METHODS: The 24-h blood pressure was monitored by a SpaceLabs 5300 device (four readings per hour during the day and three readings per hour during the night) twice, at a 4-week interval. Systolic (SBP) and diastolic blood pressure (DBP) were averaged for each hour and for the whole 24-h period, and hourly and 24-h reproducibility was quantified by the standard deviation of the mean difference (SDD) between the values obtained in the two recordings. RESULTS: The SDD of hourly SBP and DBP was much greater than that of the 24-h values and ranged widely between the hours of recording. The SDD of hourly SBP and DBP were also variably greater than the SDD of the 24-h value in another 14 untreated essential hypertensives in whom 24-h ambulatory blood pressure was monitored intra-arterially twice at a 4-week interval to calculate hourly average blood pressure on thousands rather than on three or four values per hour. CONCLUSION: Reproducibility is less for hourly than for 24-h average blood pressure. This feature (which probably depends on behavioural differences between two recordings) suggests that ambulatory blood pressure measurement partly loses its advantages for reproducibility and reduction in trial size if the results are analysed over hourly periods.

The smoothness index: a new, reproducible and clinically relevant measure of the homogeneity of the blood pressure reduction with treatment for hypertension.

OBJECTIVE: To introduce a new method, the smoothness index, for assessing the homogeneity of 24 h blood pressure reduction by antihypertensive treatment and to compare it with the trough : peak ratio; and to assess the ability of both indices to predict a reduction in the left ventricular mass index induced by treatment. PATIENTS AND METHODS: In 174 patients with essential hypertension and left ventricular hypertrophy, enrolled in the Study on Ambulatory Monitoring of Pressure and Lisinopril Evaluation (SAMPLE), aged 20-65 years, we measured clinic blood pressure, 24 h ambulatory blood pressure and the left ventricular mass index (echocardiography) before and after treatment with lisinopril at 20 mg with the addition of 12.5 or 25 mg hydrochlorothiazide as needed to reach a sufficient blood pressure reduction. The following parameters were computed for systolic and diastolic ambulatory blood pressure: (1) hourly and 24 h blood pressure averages (+/- SD) at baseline and after 3 and 12 months of treatment; (2) hourly blood pressure changes from baseline after 3 and 12 months of treatment, and their average (+/- SD) over 24 h; (3) the trough : peak ratio after 3 and 12 months of treatment; and (4) the smoothness index after 3 and 12 months of treatment Similar calculations were also performed at the end of a final study month during which active treatment was withdrawn and placebo was substituted (n = 164). RESULTS: The smoothness index for systolic and diastolic ambulatory blood pressure computed after 3 months of treatment was more closely related to its corresponding values after 12 months of treatment than the trough : peak ratio values computed after the same time periods were (r = 0.68 versus 0.38 for systolic and 0.68 versus 0.42 for diastolic blood pressure, respectively). The smoothness index showed an inverse correlation with the 24 h standard deviation of systolic and diastolic blood pressure (r = -0.25 and -0.16, P < 0.01 and < 0.05, respectively, for 12 months of treatment), while the trough : peak ratio did not (r = -0.01 to -0.12, NS). A treatment-induced reduction in the left ventricular mass index was related to the smoothness index for systolic and diastolic blood pressure (r = -0.35 and -0.32, P< 0.001 with 12 months of treatment), but not to the corresponding trough : peak ratios. CONCLUSIONS: The smoothness index identifies the occurrence of a balanced 24 h blood pressure reduction with treatment and correlates with the favourable effects of treatment on left ventricular hypertrophy better than the commonly used trough : peak ratio.

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.