Clinical relevance of ambulatory versus clinic blood pressure when evaluating antihypertensive therapy

REVIEW IN DEPTH: The evaluation of the effect of antihypertensive drugs over time has led to the increasing popularity of noninvasive ambulatory monitoring of blood pressure in the drug development process. Although not mandated by the Food and Drug Administration of the USA, from a practical standpoint new drug applications for antihypertensive agents typically include one or more studies that have used ambulatory blood pressure recordings. Ambulatory blood pressure monitoring is now used in several phases of drug development, including phase II dose-ranging studies, phase III efficacy studies, and phase IV comparative trials. The perceived benefit of the ambulatory blood pressure methodology during drug development is that it avoids observer bias, markedly reduces the effect of placebo, and may economize on sample size, especially in cross-over-designed trials. Furthermore, there is a clinical benefit of ambulatory blood pressure monitoring in the assessment of antihypertensive drugs because it allows evaluation of the effect and duration of effect of a drug during activities of daily living, including sleep.     

Utilizing ambulatory blood pressure recordings to evaluate antihypertensive drug therapy.

Until recently, the efficacy and pharmacodynamics of antihypertensive agents were assessed by resting blood pressure measurements in the doctor's office or a research clinic. The limitations of the office or clinic blood pressure measurement include the lack of representation (from recording only 1 point of time in the dosing schedule), the effects of the doctor's office on the patient's blood pressure, and, perhaps more relevant, observer bias. Ambulatory monitoring of the blood pressure has gained worldwide acceptance as an alternative method to assess antihypertensive drug efficacy and the time-effect relation of a drug. The ambulatory monitoring devices have been refined and are smaller, more precise, and more reliable than earlier recording models. Although there are no reference standards for analysis of ambulatory blood pressure data, international consensus groups are presently addressing this problem. Key roles for ambulatory blood pressure recordings in clinical trials of antihypertensive agents now include determination of the entry criteria for patients, improving the assessment of peak/trough pharmacodynamics in the patient's own environment (including nocturnal/sleep readings), and evaluating efficacy through calculation of the hypertensive burden, or blood pressure load.     

Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure

Low-dose thiazide-type diuretics are recommended as initial therapy for most hypertensive patients. Chlorthalidone has significantly reduced stroke and cardiovascular end points in several landmark trials; however, hydrochlorothiazide remains favored in practice. Most clinicians assume that the drugs are interchangeable, but their antihypertensive effects at lower doses have not been directly compared. We conducted a randomized, single-blinded, 8-week active treatment, crossover study comparing chlorthalidone 12.5 mg/day (force-titrated to 25 mg/day) and hydrochlorothiazide 25 mg/day (force-titrated to 50 mg/day) in untreated hypertensive patients. The main outcome, 24-hour ambulatory blood pressure (BP) monitoring, was assessed at baseline and week 8, along with standard office BP readings every 2 weeks. Thirty patients completed the first active treatment period, whereas 24 patients completed both. An order-drug-time interaction was observed with chlorthalidone; therefore, data from only the first active treatment period was considered. Week 8 ambulatory BPs indicated a greater reduction from baseline in systolic BP with chlorthalidone 25 mg/day compared with hydrochlorothiazide 50 mg/day (24-hour mean = -12.4+/-1.8 mm Hg versus -7.4+/-1.7 mm Hg; P=0.054; nighttime mean = -13.5+/-1.9 mm Hg versus -6.4+/-1.8 mm Hg; P=0.009). Office systolic BP reduction was lower at week 2 for chlorthalidone 12.5 mg/day versus hydrochlorothiazide 25 mg/day (-15.7+/-2.2 mm Hg versus -4.5+/-2.1 mm Hg; P=0.001); however, by week 8, reductions were statistically similar (-17.1+/-3.7 versus -10.8+/-3.5; P=0.84). Within recommended doses, chlorthalidone is more effective in lowering systolic BPs than hydrochlorothiazide, as evidenced by 24-hour ambulatory BPs. These differences were not apparent with office BP measurements.     

Benazepril versus felodipine as supplement to bendroflumethiazide: evaluation by office and ambulatory blood pressure

OBJECTIVE: To compare a combination of a thiazide diuretic and an angiotensin converting enzyme inhibitor with a thiazide diuretic and a calcium antagonist. DESIGN: A double-blind randomized trial with subjects in two parallel groups administered either 10-20 mg benazepril once daily or 5-10 mg extended-release felodipine once daily, both titrated according to diastolic office blood pressure. During run-in and all 12 weeks of the study members of both groups were administered 2.5 mg bendroflumethiazide once daily. We measured 24 h ambulatory blood pressure with thiazide alone and after 12 weeks of combination therapy. SETTING: General practices. PATIENTS: We studied 96 hypertensive patients (50 women and 46 men), aged 25-75 years, whose blood pressures were insufficiently regulated (i.e. office diastolic blood pressure >/= 95 mmHg) despite treatment with a thiazide diuretic for at least 3 months. RESULTS: The responses of office blood pressure after 12 weeks of treatment did not differ between the groups and neither did the proportions of responders. The ambulatory recordings revealed, after 12 weeks of treatment, a fall in daytime blood pressure of 16.3/10.3 mmHg in members of the benazepril group compared with a fall of 8.5/5.2 mmHg in members of the felodipine group (P < 0.001/<0.001). Analysis of variance showed that the systolic but not the diastolic office blood pressure in members of the benazepril group was significantly lower during the 12-week study period. When evaluating rising single quote, left (low)white-coat-positive' patients separately, there was a tendency for there to be a more pronounced reduction of their (normal) blood pressure with benazepril therapy. There was a significant reduction in weight of patients in the benazepril group (by 0.9 kg), but not of patients in the felodipine group. We observed no difference in side effects between the two treatment groups.CONCLUSION: Add-on therapies both with benazepril and with felodipine are effective and both drug regimens are well tolerated, but ambulatory blood pressure monitoring yielded differing results.     

Office compared with ambulatory blood pressure in assessing response to antihypertensive treatment: a meta-analysis

OBJECTIVE: To undertake a systematic review of the studies on the effect of antihypertensive treatment on ambulatory (ABP) and office blood pressure in order to obtain a differential assessment of the magnitude of the reduction in (1) office blood pressure compared with 24-h average ABP values, and (2) daytime compared with night-time average blood pressure values. DATA SOURCES: Medline search, Cochrane Library. REVIEW METHODS: This review is based on a meta-analysis (carried out according to the Quality of Reports of Meta-analyses of Randomized Controlled Trials Group statement, whenever applicable) of papers on the effect of antihypertensive drugs on blood pressure. Papers were selected if they provided information on drug-induced changes in one or both of: (1) both office blood pressure and 24-h ABP, and/or (2) both daytime and night-time average blood pressure. Additional inclusion criteria were administration of antihypertensive drugs for at least 1 week and good quality ABP, according to current guidelines. Comparison between the effect of treatment on blood pressure values was made by meta-regression of the data provided by the individual studies (weighted by their size) and by calculating differences between weighted average values obtained by pooling the results of individual papers. RESULTS: We identified 984 papers on this issue by Medline search, with no additional information from the Cochrane Library. The inclusion criteria were satisfied by only 44 papers, which were included in the final analysis. The results showed that treatment-induced reduction in blood pressure is both smaller for the 24-h average than for the office systolic and diastolic blood pressure and smaller for night-time than for daytime average diastolic blood pressure, the average ratio ranging from 0.67 to 0.75. A different ratio characterized the treatment-induced changes in office blood pressure and ABP in the Heart Outcomes Prevention Evaluation (HOPE) ABP substudy. CONCLUSIONS: The effect of antihypertensive treatment is greater on office blood pressure than on ABP, and is unevenly distributed between day and night. This suggests caution when interpreting trials on cardiovascular protection by antihypertensive treatment that are based only on office blood pressure readings, and advocates a more systematic adoption of ABP monitoring in these trials. The conflicting data provided by the main HOPE study and by the HOPE-ABP monitoring substudy on the role of blood pressure reduction in explaining the reduced event rates associated with treatment by angiotensin-converting enzyme inhibitors are a clear example of the importance of performing ABP monitoring in trials on cardiovascular protection.     

Blood pressure response to antihypertension treatment. Comparison of data obtained at the doctor's office and by ambulatory blood pressure measurement

A comparative study of clinical and ambulatory responses to antihypertensive treatment was conducted retrospectively in 69 patients with mild to moderate arterial hypertension. The patients received different drugs, but blood pressure (BP) was measured by the same methods in each of them. (a) Clinical BP was measured with a mercury manometer some time after taking the last dose of antihypertensive drug: 24 hours in patients who took one daily dose, 12 hours in those who took two daily doses. (b) Ambulatory BP was measured with a Spacelabs SPM 5200 instrument over a minimum of 24 hours. The parameters compared were: (1) BP figures recorded. Correlation was very poor as regards both SBP (r = 0.42 before treatment, r = 0.55 after treatment) and DBP (r = 0.40 and r = 0.46 respectively). The mean BP value was lower in the ambulatory group than in the clinical group (-20/-12 mmHg), the difference being slightly less marked after treatment (-12/-6 mmHg). (2) Degree of absolute reduction of BP induced by treatment. Correlation was very poor between the two methods as regards both SBP (r = 0.46) and DBP (r = 0.49). (3) Proportion of responders and non-responders to treatment, the clinical response being defined as normalization and/or more than 10 p. 100 reduction of DBP, and the ambulatory response as a significant decrease of mean diastolic value over 24 hours. Among the 69 patients studied, there were 51 concordant cases (36 responders, 15 non-responders with the two methods) and 18 discordant cases (10 clinical responders but ambulatory non-responders, 8 clinical non-responders but ambulatory responders).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacogenomics of blood pressure response to antihypertensive treatment

PURPOSE IDENTIFICATION: Inter-individual variability in blood pressure response to treatment is well documented, but a clinically useful means to distinguish responders from non-responders has been elusive. With the advent of new technologies and genomic knowledge, more investigators are seeking to identify genetic determinants of blood pressure response to therapy. STUDY SELECTION: We identified studies of candidate polymorphisms from an initial PubMed search using the MESH terms 'Hypertension: Drug Therapy' and 'Genetics' or 'Pharmacogenetics', limiting results to English-language publications on studies in human adults. We further identified specific polymorphisms of interest noted in earlier reviews and performed additional PubMed searches based on these candidate genes. Pertinent studies were further extracted from the references of studies already identified. We focused on clinical trials that measured blood pressure response to a medication or class of medications over a minimum of 4 weeks. DATA EXTRACTION: We evaluated studies looking at blood pressure response to commonly used classes of antihypertensive medications by major genetic variants. RESULTS OF ANALYSIS: Although many studies show that blood pressure response to a given class of antihypertensive medications varies by genotype for different polymorphisms, none of the genotypes identified consistently predicted blood pressure response. CONCLUSIONS: Common variants may influence response to diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, but studies of polymorphisms have generally yielded conflicting results. The inclusion of pharmacogenomic studies in large clinical trials and other more innovative investigative methods may provide greater clarity of the potential role for genotyping in the treatment of patients with hypertension.     

Gender and age effects on the ambulatory blood pressure and heart rate responses to antihypertensive therapy

BACKGROUND: The aim of this study was to assess potential differences in the 24-h antihypertensive response to treatment with the controlled-onset, extended-release (COER) calcium antagonist, verapamil in men versus women and older versus younger patients with hypertension. METHODS: Meta-analyses were performed of three prospective randomized, double-blind, placebo-controlled trials with COER-verapamil in patients with mid-stage I to stage III essential hypertension. The trials were conducted at medical clinics in the US and Canada in patients with a mean office diastolic blood pressure (BP) of 95 to 115 mm Hg on 2 consecutive weeks and a mean daytime diastolic BP >90 mm Hg. Patients were randomized to treatment with 180 to 540 mg/day of COER-verapamil (N = 273) or placebo (N = 125). Changes from baseline in ambulatory BP and heart rate after COER-verapamil were compared in men versus women and in older versus younger patients. RESULTS: Treatment with COER-verapamil caused significant reductions in 24-h and early-morning systolic and diastolic BP in all of the subpopulations as compared with placebo (P < .001). COER-verapamil induced a greater reduction in both 24-h systolic (-15.1 v -10.0 mm Hg; P < .001) and diastolic (-10.4 v -8.2 mm Hg; P = .003) BP in women compared with men. Older patients showed a greater mean reduction in 24-h diastolic BP (-10.2 v -8.2 mm Hg; P < .05) and heart rate (-5.7 v -4.4 beats/min; P < .05) compared with younger patients. Side effects were similar in all of the COER-verapamil treatment groups. CONCLUSIONS: Both gender and age were significant determinants of the response to COER-verapamil. The antihypertensive effect of verapamil is greater in women than in men and in older patients compared with younger patients.     

Guiding antihypertensive treatment decisions using ambulatory blood pressure monitoring

Compared with isolated clinic measurements, ambulatory blood pressure monitoring (ABPM) provides an insight into blood pressure (BP) changes in everyday life and an estimate of the overall BP load exerted on the cardiovascular system over 24 hours. Cross-sectional evidence suggests a direct and significant relationship between ambulatory BP and organ damage. There is also longitudinal evidence for a superior predictive value of 24-hour BP in relation to the risk for cardiovascular morbidity and mortality as opposed to clinic BP. The usefulness of ABPM in pharmacologic studies aimed at evaluating the 24-hour antihypertensive efficacy of different drugs and drug combinations is now acknowledged. Among the mathematical indices available to explore 24-hour BP coverage by treatment, the ABPM-derived smoothness index provides a superior measure of the homogeneity of BP control compared with trough:peak ratios. The main applications of clinical practice should be in identifying patients with isolated office hypertension and those who are nonresponders to treatment, in assessing coverage of the 24-hour BP profile in high-risk patients and in diagnosing suspected treatment-related hypotension.     

Clinical value of ambulatory blood pressure monitoring in the assessment of antihypertensive therapy.

Non-invasive ambulatory blood pressure monitoring (ABPM) is particularly useful for assessing the efficacy of antihypertensive drugs. It provides a large number of blood pressure readings during daytime as well as night-time, which results in a more precise assessment of prevailing blood pressure than can be obtained from sporadic measurements taken by a doctor. Because of this greater precision ABPM reduces the number of patients required in clinical trials to demonstrate differences. It also allows one to define precisely the profile of the blood-pressure-lowering effect of a given drug. Placebo has little effect on ABPM. Thus, a placebo phase is not absolutely necessary. ABPM makes it possible to evaluate the efficacy of an antihypertensive medication by analysing data for patients with a placebo effect separately from data for true responders to the medication. In everyday practice ABPM helps one to detect among patients with hypertension refractory to treatment those who exhibit controlled blood pressures outside the medical environment, thus permitting one to avoid an unnecessary step-up of treatment. In addition ABPM can also help one to identify symptoms occurring during antihypertensive treatment that are related to excessive drug-induced changes in blood pressure.     

Blood pressure measurements by the Keito machine. Evaluation versus office blood pressure by physicians

BACKGROUND: The Keito machine offers automatic measurements of blood pressure (BP), height and weight on insertion of coins and has been introduced in pharmacies. DESIGN: Cross-sectional study comparing automatic BP measurements by the Keito machine to office BP measurements by physicians. METHODS: Patients scheduled for pre-catheterisation screening participated in the study. Their BP was first measured using the Keito machine, then by physicians. Office BP was recorded as the last of three consecutive BP measurements recorded with one-min intervals after a five-min rest in the sitting position. In a sub-study BP was measured simultaneously during the Keito measurement by a physician. RESULTS: In 390 consecutive patients average BP was significantly lower with the Keito machine compared to office BP measurements made by the physicians (136/75+/-19/8 mmHg versus 141/79+/-21/10 mmHg, both p<0.001). The correlation coefficient (r) was 0.56 (p<0.001) for systolic BP (SBP) and 0.53 (p<0.001) for diastolic BP (DBP). Bland-Altman analysis showed a mean difference (+/-2 SD) for SBP and DBP of -5 (+/-37) and -4 (+/-17) mmHg, respectively. When defining hypertension (HT) as office SBP> or =140 and/or DBP> or =90 mmHg, the Keito method diagnosed 83% of the systolic and 62% of the diastolic hypertensive population correctly. The classification of systolic and diastolic normotensive was correct in 61% and 86%, respectively. CONCLUSION: Agreement between office and Keito BP is poor. The Keito machine underestimates SBP on average by 5 mmHg and DBP by 4 mmHg, which may be of significance for diagnosing HT and starting anti-hypertensive therapy. However, the difference can be much larger in individual patients. Therefore, the Keito machine cannot be recommended for medical screening of HT or as a replacement for follow-up by physicians.     

Evaluation of antihypertensive therapy by ambulatory blood pressure monitoring and establishment of the level of antihypertensive goal on the circadian rhythm of blood pressure

We have developed a new method for the evaluation of antihypertensive therapy on the circadian rhythm of blood pressure and attempted to determine the indications for antihypertensive therapy and the level of antihypertensive goal. Blood pressures were measured for 24 hours by the use of ambulatory blood pressure monitoring using 630 (ABPM-630) in 50 normotensives, 50 untreated hypertensives and 50 hypertensives undertreatment with various antihypertensive drugs (110 males and 40 females, with a mean age of 53.4 +/- 13.3 yrs). Blood pressure profiles were prepared for determination of the hyperbaric and hypobaric indexes. According to the WHO's definitions for blood pressure, the hyperbaric index was defined as the area above 140 mmHg in systolic blood pressure or 90 mmHg in diastolic blood pressure, and the hypobaric index, as the area below 100 mmHg or 60 mmHg, respectively. The criteria of the hypobaric index was obtained from the mean basal blood pressure (the lowest blood pressure during sleep) of the 50 normotensives. The mean hyperbaric index of the 50 normotensives was 20.4 +/- 40.2/5.5 +/- 15.3 (systole/diastole) mmHg.hour/day and the mean hypobaric index, 12.2 +/- 22.5/9.0 +/- 24.0 mmHg.hour/day. The 50 untreated hypertensives showed a mean hyperbaric index of 281.8 +/- 197.0/156.0 +/- 126.1 mmHg.hour/day and a mean hypobaric index of 0.1 +/- 0.6/0.3 +/- 1.5 mmHg.hour/day. Comparison of the indexes before and after treatment with various antihypertensives showed that a decrease in the hyperbaric index without an increase in the hypobaric index was the most optimal reduction of blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of agreement between office and ambulatory blood pressure responses to hydrochlorothiazide

BACKGROUND: Differences between the antihypertensive responses to drug therapy measured by office blood pressure (OBP) and ambulatory blood pressure monitoring (ABPM) techniques have been noted but rarely analyzed. We studied whether the OBP and 24-h ABPM responses to hydrochlorothiazide differ and, if so, the relevance of these differences. METHODS: The OBP and ABPM responses to hydrochlorothiazide (25 mg/d, for 4 weeks) were measured in 228 subjects with essential hypertension, and mean responses were compared between methods using the Student paired t test. To assess variation in the agreement between OBP and ABPM responses among subjects, the limits of agreement were calculated as the mean difference between OBP and ABPM responses +/-2 standard deviations. RESULTS: The mean systolic OBP response was 4.8 mm Hg greater than the response measured by ABPM (-14.3 v -9.5 mm Hg, P < .001), and the mean diastolic OBP response was 2.1 mm Hg greater than the response measured by ABPM (-7.5 v -5.5, P < .001). The limits of agreement between the OBP and ABPM responses ranged from -18.7 to +28.2 mm Hg for systolic response and from -12.9 to +17.1 mm Hg for diastolic response. The systolic and diastolic OBP and ABPM responses were in opposite directions in 22.8% and 23.7% of the subjects, respectively. CONCLUSIONS: Compared to ABPM, OBP overestimates the mean systolic and mean diastolic blood pressure responses to hydrochlorothiazide. Variation among subjects in the magnitude and direction of responses renders OBP an unreliable predictor of ABPM responses.     

Assessment of antihypertensive efficacy by non-invasive ambulatory blood pressure monitoring

The session devoted to the usefulness of non-invasive ambulatory blood pressure monitoring (ABPM) in the evaluation of antihypertensive therapy allowed us to discuss a number of important issues. ABPM emerged as a widely accepted technique to measure blood pressure in clinical trials. Actually, it was generally considered to provide more valuable information than do conventional blood pressure readings obtained sporadically by a doctor. However, still debated was the way of analysing ABPM recordings. This was particularly true with respect to the proposal of considering separately responders and non-responders when assessing the quality of blood pressure control achieved during treatment.