Theodore D. Mountokalakis

Reproducibility of home, ambulatory, and clinic blood pressure: Implications for the design of trials for the assessment of antihypertensive drug efficacy

Abstract Background The aims of this study were to compare the reproducibility of blood pressure (BP) measured in the clinic (CBP), at home (HBP), and by ambulatory monitoring (ABP), and to assess its implications on the accuracy of antihypertensive drug trials. Methods A total of 133 untreated subjects with elevated CBP were assessed with repeated measurements of CBP (five visits within 3 months), HBP (6 workdays within 2 weeks), and ABP (twice, 2 weeks apart). The reproducibility of CBP (one visit), HBP (2 days), and ABP (24 h) was quantified using the SD of differences (SDD) between repeated measurements. The number of subjects required in a comparative trial of two drugs was calculated for each measurement method. Results We found that HBP provided the lowest SDD values (6.9/4.7 mm Hg, systolic/diastolic, compared with 8.3/5.6 for ABP and 11.0/6.6 for CBP). For a parallel trial aiming to detect a difference in the effect of two drugs of 10 mm Hg systolic BP, 51 subjects would be required when using CBP compared with 29 using ABP and 20 using HBP (73, 53 and 37 subjects, respectively, for the detection of a 5 mm Hg difference in diastolic BP). Conclusions The study shows that HBP seems to have superior reproducibility compared with both CBP and ABP. In addition, HBP can improve the accuracy of antihypertensive drug trials, thereby reducing the sample size required.

Self-monitoring of blood pressure at home: how many measurements are needed?

Objective To determine the minimum number of self-measurements of blood pressure at home (HBP) necessary to provide the maximum clinically important benefit. Methods Hypertensive patients were randomly allocated to monitor HBP for 2 weeks (6 work days, duplicate measurements, twice daily) or ambulatory blood pressure for 24 h. The alternative measurement was then performed. Clinic blood pressure was measured at the beginning and the end of the study. Criteria for reliability of HBP were the stabilization of mean HBP, its variability (SD) and the correlation coefficient r for relationship of HBP with ambulatory blood pressure. The reproducibility of HBP was quantified using test–re-test correlations and the SD of differences between average HBP values of different days. Results We studied 189 patients (79 being administered stable antihypertensive treatment). Average HBP (137.5 ± 16.2/85.9 ± 9.9 mmHg) was lower than average clinic blood pressure (P < 0.001) and higher than 24 h and night-time ambulatory blood pressures (P < 0.001). There was no difference between HBP and daytime ambulatory blood pressure. On day 1 HBP was higher than it was on each of days 2–6, with no difference among days 2–6. When data for the initial day for monitoring of HBP were excluded from analysis, average HBP was reduced. Only a modest improvement in the reliability of HBP on day 2 (reductions in mean HBP and its SD and an increase in r with ambulatory blood pressure) was achieved by averaging more readings taken on succeeding days. At least two monitoring days were needed for the reproducibility of HBP to be superior to that of clinic blood pressure. Conclusions These results suggest that determining average HBP of the second and third work days, is the minimum programme that provides a reliable estimate of HBP.

Parallel Morning and Evening Surge in Stroke Onset, Blood Pressure, and Physical Activity

Background and Purpose— A circadian variation with a morning peak on waking and arising is known to occur in both blood pressure (BP) and cardiovascular event onset. A second peak in BP has been described to occur after an afternoon sleep (siesta). This study was designed to investigate the hypothesis that the 2-peak diurnal variation of BP is dependent on physical activity and occurs in parallel with the diurnal variation of stroke onset. Methods— The diurnal variation of stroke onset was compared with the diurnal variation of BP, pulse rate (PR), and physical activity in 3 independent groups of Greek hypertensives 51 to 80 years of age (633 stroke patients, 379 subjects with 24-hour ambulatory BP monitoring, and 50 subjects with 24-hour physical activity monitoring through wrist devices). Results— The diurnal variation of stroke onset, BP, and PR all showed 1 morning and 1 evening peak with a decline in the afternoon and at night that occurred in parallel with the diurnal variation in physical activity (P <0.001 for differences among morning, afternoon, evening, and nighttime intervals in BP, PR, activity, and stroke). The afternoon decline in BP, PR, and activity was significant only in subjects with a siesta. Conclusions— The 2-peak diurnal variation in stroke onset occurred in parallel with the variation in BP, PR, and physical activity. These data support the hypothesis that an abrupt change in physical activity is not only a major determinant of the 2-peak diurnal variation of BP but also an important triggering factor for a cerebrovascular event.

White coat effect detected using self-monitoring of blood pressure at home: comparison with ambulatory blood pressure.

The objective of the study was to investigate whether home blood pressure (HBP) is a reliable alternative to ambulatory blood pressure (ABP) for the detection of the white coat effect (WCE). Hypertensive patients were randomized to measure HBP for 2 weeks or ABP for 24 h. The alternative measurement was then performed. Clinic blood pressure (CBP) was measured in the beginning and end of the study. Subjects with a difference of > or = 20 mm Hg systolic or > or = 10 mm Hg diastolic BP between CBP and awake ABP or CBP and HBP, were classified as clinic reactors. A total of 189 patients completed the study (79 on stable antihypertensive treatment). There was no difference in the magnitude of WCE assessed using the ABP or the HBP method (mean discrepancy, systolic BP: -1.5 +/- 11.7 mm Hg, 95% CI -3.2, 0.2; diastolic BP: 0.9 +/- 7.0, 95% CI -0.1, 1.9). A strong association existed between WCE calculated using the HBP or the ABP method (r = 0.64/0.59 systolic/diastolic, P < .001). The proportion of patients classified as clinic reactors was identical using the HBP or the ABP method (25.9%). Agreement between methods in the classification of clinic reactors was found in 147 patients (78%). The sensitivity and specificity of the HBP method to classify correctly clinic reactors (ABP method used as the standard) were 57% and 85%, respectively, whereas its positive and negative predictive value were 57% and 85%. These results indicate that HBP is not appropriate as an alternative to ABP diagnostic testing in the detection of WCE. Nevertheless, HBP appears useful as a screening test for the detection of this phenomenon.

Diagnosis of hypertension using home or ambulatory blood pressure monitoring: comparison with the conventional strategy based on repeated clinic blood pressure measurements.

Objective To investigate whether measurement of blood pressure at home (HBP) and by ambulatory monitoring (ABP) are reliable alternatives to the traditional strategy for the diagnosis of hypertension based on blood pressure measurement on repeated clinic visits (CBP). Design Comparison of the diagnosis of hypertension based on HBP (on six workdays) or ABP monitoring (two occasions) with that based on CBP (five visits within 3 months). Setting Outpatient hypertension clinic. Participants We enrolled 133 individuals with a diastolic CBP of 90–115 mmHg on the initial visit. Main outcome measures CBP, HBP and ABP values, and the diagnosis of hypertension. Results Hypertension was diagnosed in 70, 63 and 56% of individuals using the CBP, ABP and HBP methods respectively (P = 0.04). Agreement in the diagnosis of hypertension between all three methods was found in 59% of individuals. Disagreement between CBP and ABP was found in 27%, between CBP and HBP in 29% and between ABP and HBP in 26% of individuals. The sensitivity, specificity and positive and negative predictive values of ABP to diagnose hypertension correctly were 76, 67, 85 and 53% respectively; for HBP the respective values were 69, 77, 88 and 51%. The same parameters for HBP compared with ABP in the detection of white-coat hypertension were 61, 79, 48 and 86% respectively. Conclusions Indiscriminate use of HBP or ABP monitoring in the evaluation of all individuals with high blood pressure will probably result in confusion and therefore should be discouraged. However, in the detection of white-coat hypertension, HBP appears to be useful as a screening test, which, if positive, requires confirmation with ABP monitoring.

Prevalence, awareness, treatment, and control of hypertension in Greece The Didima study

To assess the prevalence and the levels of awareness, treatment, and control of hypertension in the rural population of Greece, a cross-sectional survey of the total population age > or =18 years of the village Didima was conducted. The survey included an interview and blood pressure (BP) measurement on two clinic visits. Hypertension was defined as systolic BP > or = 140 mm Hg and or diastolic BP > or = 90 mm Hg or current treatment with antihypertensive drugs. The same BP threshold was used for the assessment of hypertension control. A total of 694 inhabitants participated (response rate 76.4%), and 665 were analyzed. The prevalence of hypertension was 28.4% (men 30.2%, women 27.1%). Of the subjects age > or =65 years, 50% had hypertension. Although 73% of participants were measuring their BP at least once a year, overall, 39.2% of hypertensives were unaware of the diagnosis (men 50%, women 30.5%), 6.3% were aware but not treated (men 4.8%, women 7.6%), 27.5% were treated but not controlled (men 22.6%, women 31.4%), and 27% were treated and controlled (men 22.6%, women 30.5%). These results suggest that, in the rural population of Greece, hypertension is a common risk factor with considerable potential for improvement in levels of control.

Additive hypotensive effect of angiotensin-converting enzyme inhibition and angiotensin-receptor antagonism in essential hypertension

The study was designed to assess the antihypertensive effect of combined angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor (AT1) antagonism in patients with essential hypertension. Twenty patients with uncontrolled ambulatory diastolic blood pressure (BP) after 6 weeks of ACE inhibitor monotherapy (benazepril, 20 mg, o.d.) were randomized to receive double-blind valsartan, 80 mg, o.d. (AT1 antagonist) or matching placebo for 5 weeks while continuing to receive background benazepril. Then patients crossed over to the alternative regimen for a second 5-week period. The 24-h ambulatory BP was monitored on the final day of the benazepril monotherapy period and on the final day of each double-blind treatment period. Valsartan added to benazepril produced a significant antihypertensive effect with a benefit over placebo of 6.5 +/- 12.6/4.5 +/- 8.0 mm Hg (systolic/diastolic) for average awake ambulatory BP (p < 0.05), 7.1 +/- 9.4/5.6 +/- 6.5 mm Hg for asleep BP (p < 0.01), and 6.8 +/- 9.7/4.9 +/- 6.8 mm Hg for average 24-h ambulatory BP (p < 0.01). Pulse rate was unaffected. Plasma active renin was higher on the benazepril-valsartan combination compared with benazepril-placebo (p < 0.05). There was no change in routine biochemical variables when valsartan was added to benazepril. Six patients reported mild dizziness or fatigue (three also with placebo). These data suggest that in hypertensive patients uncontrolled with an ACE inhibitor, the addition of an AT1 antagonist provides a powerful and safe antihypertensive drug combination.

Reproducibility of home and ambulatory blood pressure in children and adolescents.

ObjectiveTo evaluate the reproducibility of blood pressure measured at home (HBP) in comparison with ambulatory (ABP) and clinic blood pressure (CBP) in children and adolescents. Participants and methodsIndividuals aged 8–17 years who had been referred for elevated CBP were included. CBP was measured at two visits, HBP on 5 days and ABP for 24 h. A second session including all the above measurements was performed after 8 weeks. The reproducibility of CBP (second visit of each session), HBP (average of days 2–5 of each session) and ABP (average 24-h, awake and asleep) was quantified using test–retest correlations coefficients (r) and the standard deviation of differences (SDD) between repeated measurements. ResultsSixteen individuals were included [mean age 13.3±2.9 (SD)] years, range 8–17, nine boys]. According to Task Force CBP criteria, eight were classified as hypertensives, three as high normal and five as normotensives. The reproducibility of HBP (systolic/diastolic r, 0.74/0.82, SDD 7.0/4.3) was superior to that of CBP (r, 0.63/0.80, SDD 10.4/6.3). However, ABP appeared to provide the most reproducible values (r, 0.87/0.84, SDD 5.5/4.3 for 24-h ABP; r, 0.85/0.76, SDD 5.9/5.0 for awake; r, 0.76/0.79, SDD 7.0/5.0 for asleep ABP). Aspects of the diurnal ABP variation were poorly reproducible (r, 0.62/0.14, SDD 6.8/5.5 for awake-asleep ABP difference; r, 0.55/0.26, SDD 0.07/0.11 for awake : asleep ratio). ConclusionThese data suggest that in children and adolescents home blood pressure measurements are more reproducible than clinic measurements. However, 24-h ambulatory monitoring appears to provide the most reproducible blood pressure values.

Home blood pressure normalcy: The Didima study

To evaluate reference values of home blood pressure (HBP) a cross-sectional community study was conducted on 694 adult subjects (aged > or = 18 years) of the village Didima in southern Greece (participation rate 76.4%). Clinic blood pressure (CBP) was measured on two visits (triplicate measurements, mercury sphygmomanometer) and HBP on 3 workdays (duplicate morning and evening measurements, oscillometric devices; Omron HEM 705CP). After exclusion of 132 subjects (103 treated hypertensives and 29 with incomplete data), 562 subjects were analyzed (mean +/- SD aged 51.2 +/- 17.2 years, 42.7% men). Average HBP (120.0 +/- 17.8/72.6 +/- 8.8 mm Hg, systolic/diastolic) was strongly correlated (P < .0001) with CBP (118.7 +/- 17.7/73.8 +/- 10.5 mm Hg). Systolic CBP was 1.3 mm Hg lower than HBP (P < .01, 95% confidence interval 0.4, 2.2), whereas diastolic CBP was 1.2 mm Hg higher than HBP (P < .0001, 95% confidence interval 0.6, 1.7). The threshold of HBP normality determined using three different approaches was 1) 139.7/83.0 mm Hg (systolic/diastolic) using the distribution criterion (95th percentile of the HBP distribution among 476 normotensive subjects); 2) 139.7/85.8 mm Hg using the correspondence criterion (the percentiles of the CBP distribution that correspond to CBP > or = 140/90 mm Hg were estimated, and the levels of BP that correspond to these same percentiles on the HBP distribution were calculated); and 3) 137.4/82.7 mm Hg using the regression criterion (calculation of the levels of HBP that correspond to CBP of 140/90 mm Hg using the regression equation between HBP and CBP). Overall, the findings of the three criteria suggest that average HBP < 137/82 mm Hg might be considered as probably normal, > 140/86 mm Hg as probably abnormal, and within these limits as borderline. Until mortality-based prospective data are available, this approach might be useful in the interpretation of HBP in clinical practice.

Does the antihypertensive response to angiotensin converting enzyme inhibition predict the antihypertensive response to angiotensin receptor antagonism

To test the hypothesis that the antihypertensive response to angiotensin converting enzyme (ACE) inhibition can predict the response to angiotensin II type I receptor (AT1R) antagonism, 33 hypertensive patients were randomized to receive lisinopril (20 mg) or losartan (50 mg) for 5 weeks. Patients were then crossed-over to the alternative treatment for a second 5-week period. Twenty-four-hour ambulatory BP (ABP) was measured before randomization and on the final day of each period. The agreement in ABP response between the two drugs was assessed using the following approaches: Subjects were classified as responders and nonresponders using as a threshold an arbitrary level of response (ABP fall > or = 10 mm Hg systolic or > or = 5 mm Hg diastolic) or the median ABP response achieved by each of the drugs. Disagreement between the two drugs in the responders-nonresponders classification was expressed as the proportion of subjects whose ABP responded to one of the drugs only. Lisinopril was more effective than losartan in reducing ABP (mean difference 4.7+/-8.1/3.3+/-5.7 mm Hg, systolic/diastolic, P < .05). Disagreement in the antihypertensive response between the two drugs was found in 39%/33% of subjects for systolic/diastolic ABP using the arbitrary response criterion (33%/39% using the median response criterion). Significant correlations were found between the responses to lisinopril and losartan (r = 0.47/0.59, systolic/diastolic, P < .01). We conclude that in more than one third of hypertensive subjects, the BP response to ACE inhibition fails to predict the response to AT1R antagonism and vice versa. These data suggest that there are differences between these two drug classes that are not only of theoretical but also of practical significance.