- Email: [email protected]
Low dose bendrofluazide (1.25 mg) effectively lowers blood pressure over 24 h
AJH
1999;12:528 –531
Low Dose Bendrofluazide (1.25 mg) Effectively Lowers Blood Pressure Over 24 h Results of a Randomized, Double-Blind, Placebo-Controlled Crossover Study M. Ivan Wiggam, Patrick M. Bell, Brian Sheridan, Anona Walmsley, and A. Brew Atkinson
Previous studies indicate that low dose bendrofluazide (1.25 mg/day) has no deleterious effect on insulin sensitivity in contrast to conventional doses. To evaluate the antihypertensive effect of 1.25 mg bendrofluazide across 24 h, we studied 12 subjects in a randomized, double blind, cross-over trial, comprising 8 weeks of either 1.25 mg/day bendrofluazide or placebo. Twenty-four-hour blood pressure averages were significantly lower after bendrofluazide compared with placebo (systolic
I
n the treatment of hypertension the role of therapy is not only to lower blood pressure but also to reduce overall cardiovascular risk.1,2 Given evidence linking insulin resistance and hyperinsulinemia to atheromatous disease,3,4 it has been argued that antihypertensive agents with neutral or beneficial effects on insulin resistance should be used in preference to those with known harmful effects.2 Since their introduction in 1957, thiazide diuretics have remained popular as effective, well tolerated once-daily therapy for arterial hypertension. In large prospective studies of mild hypertension, they have
From the Sir George E. Clark Metabolic Unit (MIW, PMB, ABA), and the Regional Endocrine Laboratory, Royal Victoria Hospital (BS), Belfast, and Lisburn Health Centre (AW), Lisburn, County Antrim, Northern Ireland. During the course of these studies Dr. Wiggam was the recipient of a Royal Victoria Hospital Research Fellowship. Address correspondence and reprint requests to Professor A. B. Atkinson, Sir George E. Clark Metabolic Unit, Royal Victoria Hospital, Belfast, BT12 6BA, Northern Ireland.
© 1999 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
125 6 4 v 136 6 3 mm Hg, P < .005; diastolic: 78 6 2 v 85 6 2 mm Hg, P < .01). Trough:peak ratios were 0.67 6 0.07 for systolic and 0.72 6 0.15 for diastolic blood pressure reduction. In conclusion, 1.25 mg bendrofluazide daily produced a useful antihypertensive effect across the full 24-h period. Am J Hypertens 1999;12:528 –531 © 1999 American Journal of Hypertension, Ltd. KEY WORDS:
Thiazide diuretics, ambulatory blood pressure monitoring, hypertension, bendrofluazide.
produced consistent benefit, particularly in reducing the risk of stroke.5 However the reduction in excess risk of coronary heart disease has been less than expected.5 One possible explanation for this is that the benefits of blood pressure reduction were offset by adverse effects of therapy on lipid profiles, glucose tolerance, and insulin sensitivity. It is now well recognized that thiazide-induced effects on plasma glucose, lipids, and lipoproteins are dose-dependent and can be minimized by using lower doses.6 We have previously shown that low dose bendrofluazide (1.25 mg daily) has no deleterious effects on peripheral or hepatic insulin sensitivity, in contrast to conventional dose bendrofluazide (5 mg daily), in patients with essential hypertension7 and in patients with hypertension and type 2 diabetes mellitus.8 More recently we have also found the intermediate dose of 2.5 mg daily to adversely affect insulin action in hypertensive patients with type 2 diabetes.9 Before low dose bendrofluazide (1.25 mg daily) can be recommended for routine clinical use, it is neces0895-7061/99/$20.00 PII S0895-7061(98)00268-4
AJH–MAY 1999 –VOL. 12, NO. 5
ANTIHYPERTENSIVE EFFICACY OF LOW DOSE BENDROFLUAZIDE
sary to consider its efficacy. Although previous studies using clinic blood pressure measurements at the end of dose interval suggest that the hypotensive effect of low dose bendrofluazide is similar to that of higher doses,6 – 8 no studies have assessed 24-h blood pressure control with low dose bendrofluazide and its trough:peak ratio has not been determined. Homogenous 24-h blood pressure control is now considered an important goal of therapy, and determination of the trough:peak ratio is required by the US Food and Drug Administration for all new antihypertensive agents. To provide this information for low dose bendrofluazide (1.25 mg daily) we have conducted a randomized, placebo-controlled crossover trial using ambulatory blood pressure monitoring under standardized conditions. SUBJECTS AND METHODS Subjects White hypertensive patients of western European origin, aged ,65 years, were recruited from general practice. Exclusion criteria were as follows: cardiac, hepatic, or renal disease; diabetes mellitus; drug therapy that might affect blood pressure; secondary hypertension and clinic diastolic blood pressure outside the range of 95–110 mm Hg after a 6-week placebo run-in. All patients gave written informed consent, and the protocol was approved by the Ethics Committee of the Queen’s University of Belfast. Study Design A randomized, double blind crossover design was employed. Antihypertensive therapy was discontinued and placebo substituted during a 6 week run-in. At the end of this period only those patients with clinic diastolic blood pressure of $ 95 mm Hg were eligible to continue. Patients were randomized to receive either placebo or bendrofluazide 1.25 mg daily for an 8-week period. Patients then proceeded to a 6-week placebo washout, after which they crossed over to receive the alternative, randomly allocated bendrofluazide or placebo for a further 8 weeks. Assessment Throughout the trial patients were seen by the same investigator, during and at the end of each treatment period. Patients attended while fasting, before taking their study medication. Clinic blood pressure was measured using a Hawksley random zero sphygmomanometer and the mean of three readings was used. At each visit venous blood was drawn for measurement of plasma glucose, serum urea, creatinine, electrolytes, glycated hemoglobin, hemoglobin, and lipid concentrations. At baseline (after the 6-week placebo run-in) and at the end of the two 8-week treatment periods, 24-h ambulatory blood pressure measurements were performed using the Tycos QuietTrak ambulatory moni-
529
tor (Welch Allyn, Skaneatles Falls, NY)10 under standardized conditions. Patients were admitted to the hospital on the evening before assessment and halfhourly blood pressure recordings commenced to allow familiarization with the equipment. At set-up, simultaneous measurements were obtained by the monitor and an investigator using a T-tube connected to a mercury sphygmomanometer. Device inaccuracy was excluded by ensuring that consecutive systolic and diastolic readings obtained by the device differed by no more than 5 mm Hg from those obtained by the investigator. Study medication was administered by the nursing staff at 8 am on the morning after admission and half-hourly blood pressure monitoring was continued for a further 24 h. After each recording session, ambulatory blood pressure data were down-loaded to a personal computer. A software package (QTrak Version 1.0, Tycos Instruments) was used to edit the data based on predetermined criteria for the identification of erratic readings. On average, 97% of the data for each patient was available for further analysis after editing. Data for the 24 h of recording after drug administration were analyzed. Night blood pressure was taken as the recordings from midnight to 6 am, which corresponds to the normal rest period on the hospital ward. Hourly blood pressure averages were determined for individual patients and the trough and peak of the antihypertensive effect computed as the difference between blood pressure profiles on placebo and active treatment.11 For peak effect the hour with maximum blood pressure change between 2 and 8 h after drug administration was selected. The drug effect during this selected hour was averaged with that of the adjacent hour (within the 2 to 8 h interval) in which the effect was most evident.11 Trough response was derived by averaging mean blood pressure changes from the final 4 h of the 24-h profile. Individual trough:peak ratios were calculated for responders (peak effect . 10 mm Hg) and the mean ratio in responders was determined.11 Trough: peak ratio for the group as a whole was also calculated by an alternative method in which the mean of individual troughs is divided by the mean of individual peaks for the group.12 Statistical Aspects The number of subjects provided 95% power to detect a 7 mm Hg change in average 24-h diastolic blood pressure at the 5% significance level. Statistical analysis was performed using the Hills and Armitage method as previously described.7 This method enables comparisons of the effects of bendrofluazide and placebo to be adjusted for any period effects. No carry-over effect was detected for any variable measured and there was therefore no necessity to analyze any variables as a parallel study.
530
AJH–MAY 1999 –VOL. 12, NO. 5
WIGGAM ET AL
Results are expressed as means and standard errors of the mean (SEM). Significance was taken as P , .05. RESULTS Of 15 patients enlisted for the study, 13 fulfilled the entry criteria (in one subject the diastolic blood pressure exceeded a predefined limit of 110 mm Hg; the other was found to have proteinuria and was excluded). One additional patient withdrew during the first treatment period for reasons unconnected with the study. The 12 remaining patients completed the protocol (three male, nine female; mean age 53 6 3) years; body mass index 31.5 kg/m2). Patient compliance was good, with . 95% of the study medication being consumed by all participants. Mean 24-h systolic pressure after bendrofluazide was 125 6 4 mm Hg, compared with 138 6 5 mm Hg at baseline (P , 0.05) and 136 6 3 mm Hg after placebo (P , .005). Mean 24-h diastolic pressure after bendrofluazide was 78 6 2 mm Hg, compared with 86 6 3 mm Hg at baseline (P , .05) and 85 6 2 mm Hg after placebo (P , 0.01). Both day and night blood pressure averages were significantly lower after bendrofluazide compared with placebo. Systolic and diastolic blood pressure profiles across the 24-h period showed homogenous blood pressure reduction with low dose bendrofluazide, as shown by Figure 1. Trough:peak ratios in responders averaged 0.67 6 0.07 for systolic blood pressure and 0.72 6 0.15 for diastolic blood pressure (peak blood pressure response $ 10 mm Hg; n 5 9 for systolic blood pressure, n 5 7 for diastolic blood pressure). The trough:peak ratio calculated from the mean of individual trough and peak effects from the whole group was 0.57 for both systolic and diastolic blood pressure. Serum potassium was marginally lower after bendrofluazide compared with placebo (3.8 6 0.1 v 4.1 6 0.1 mmol/L, P , .05), although in no case did the level fall below 3.4 mmol/L. Bendrofluazide had no effect on serum urea and creatinine levels. Serum urate levels were slightly higher after bendrofluazide (0.37 6 0.03 v 0.33 6 0.02 mmol/L, P , .005), although no subject developed clinical gout. No significant changes in fasting glucose or glycated hemoglobin concentrations were found. Total cholesterol levels were slightly lower after bendrofluazide compared with placebo (5.3 6 0.02 v 5.5 6 0.03 mmol/L, P , .005). DISCUSSION Increasingly, in the treatment of essential hypertension, emphasis is being placed on overall cardiovascular risk reduction as well as on blood pressure control.1,2 Choice of antihypertensive agent is influenced by known effects on various parameters including insulin sensitivity, which often clusters with a number
FIGURE 1. Systolic (SBP) and diastolic (DBP) blood pressure profiles after placebo and 1.25 mg bendrofluazide (2-hourly averages) demonstrate uniform blood pressure reduction throughout the 24-h interval after drug administration (8 am in all cases).
of vascular risk factors and may play a central role in the process of atherogenesis.3,4,13 Conventional doses of thiazide diuretic adversely affect insulin sensitivity,7–9 whereas low dose bendrofluazide (1.25 mg daily) has been shown by glucose clamp methodology to have no harmful effect on either peripheral or hepatic insulin action.7,8 In this double blind, placebo-controlled, crossover study we have demonstrated that once-daily bendrofluazide 1.25 mg lowers average 24-h ambulatory blood pressure by 11/7 mm Hg, a reduction that is comparable to that reported with other well accepted antihypertensive agents. Trough:peak ratios calculated by alternative methods indicate a sustained antihypertensive effect throughout the 24-h dose interval. One previous study reported a significant reduction in 24-h blood pressure averages with hydrochlorothiazide 12.5 mg daily with a trough:peak ratio of 0.57.14 This study, which was limited to black South African patients, did not have a randomized placebo control and relied on comparisons against a baseline placebo period.14 By contrast, the present study used a randomized, double blind, placebo-controlled design, and included only white subjects. To the best of our knowledge, the present study is the first to character-
AJH–MAY 1999 –VOL. 12, NO. 5
ANTIHYPERTENSIVE EFFICACY OF LOW DOSE BENDROFLUAZIDE
ize the 24-h antihypertensive effect of bendrofluazide 1.25 mg—the only low dose thiazide the neutrality of which, in relation to insulin resistance, has been verified by glucose clamp methodology.7,8 In addition to a randomized placebo period, the present study involved ambulatory blood pressure recording under carefully controlled conditions, to maximize reproducibility and increase the precision of placebo-drug comparisons. These design features have previously been recommended for the accurate determination of trough:peak ratios.15 Although the US Food and Drug Administration has recommended for several years that new antihypertensive agents have a trough:peak ratio of $ 50%, there is a lack of standardized guidelines as to how trough:peak ratios should be calculated. In a large study, Omboni et al specifically addressed a number of methodological issues concerning the calculation of trough:peak ratios and suggested that ratios should ideally be calculated in individual patients but be limited to those who respond to treatment.11 It is argued that avoidance of nonresponders removes values that are often erratic and have no pharmacodynamic significance. However, ratios derived from responders only have statistical limitations and should be supported by trough:peak ratios calculated from group means of all the individual troughs and peaks.12 In the present study we have demonstrated acceptable trough:peak ratios with low dose bendrofluazide using both of these methods. In the present study a small, but significant, decrease in serum potassium levels was found in association with low dose bendrofluazide. This was not observed in previous, larger studies involving a longer duration of treatment with 1.25 mg bendrofluazide.6,8,9 In any case the small changes seen in the present study are unlikely to be of biologic significance. In summary, we have shown in a randomized, double blind, placebo-controlled study that 1.25 mg bendrofluazide daily produces an average fall in blood pressure of 11/7 mm Hg across a 24-h period. The trough:peak ratios in responders were excellent at 0.67 for systolic blood pressure reduction and 0.72 for diastolic blood pressure reduction. This low dose of bendrofluazide, which has no adverse effects on peripheral or hepatic glucose metabolism, can now be recommended as a useful agent in the management of essential hypertension, used either alone or in combination. ACKNOWLEDGMENTS We thank Mrs. M. McFarland and Mrs. H. Creighton, Pharmacy Department, Royal Victoria Hospital, for help with
531
randomization and drug dispensing and Dr. C. C. Patterson, Department of Community Medicine and Medical Statistics, the Queen’s University of Belfast, for statistical advice. We are grateful to Mrs. M. Loughran for secretarial assistance.
REFERENCES 1.
Kaplan NM: Antihypertensive therapy to maximally reduce coronary risk. Am Heart J 1993;125:1487–1493.
2.
Reaven GM: Treatment of hypertension: focus on prevention of coronary heart disease. J Clin Endocrinol Metab 1993;76:537–540.
3.
Howard G, O’Leary D, Zaccaro D, et al: Insulin sensitivity and atherosclerosis. Circulation 1996;93:1809–1817.
4.
Despre´s J-P, Lamarche B, Mauriege P, et al: Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:952–957.
5.
Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827– 838.
6.
Carlsen JE, Kober L, Torp-Pedersen C, et al: Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. Br Med J 1990; 300:975–978.
7.
Harper R, Ennis CN, Sheridan B, et al: Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension. Br Med J 1994; 309:226 –230.
8.
Harper R, Ennis CN, Heaney AP, et al: A comparison of the effects of low- and conventional dose thiazide diuretic on insulin action in hypertensive patients with NIDDM. Diabetologia 1995;38:853– 859.
9.
Hunter SJ, Wiggam MI, Ennis CN, et al: Comparison of effects of captopril, used either alone or in combination with a thiazide diuretic, on insulin action in hypertensive type 2 diabetic patients: a double-blind crossover study. Diabet Med (in press).
10.
White WB, Susser W, James GD, et al: Multicenter assessment of the Quiet Trak ambulatory blood pressure recorder according to the 1992 AAMI guidelines. Am J Hypertens 1994;7:509 –514.
11.
Omboni S, Parati G, Zanchetti A, et al: Calculation of trough:peak ratio of antihypertensive treatment from ambulatory blood pressure: methodological aspects. J Hypertens 1995;13:1105–1112.
12.
Zanchetti A, on behalf of the Italian Nifedipine GITS Study Group: Trough:peak ratio of the blood pressure response to dihydropyridine calcium antagonists. J Hypertens 1994;12(suppl 8):S97–S106.
13.
Stout RW: Insulin and atheroma: 20 year perspective. Diabetes Care 1990;13:631– 654.
14.
Skoularigis J, Strugo V, Chopamba A, et al: Low dose hydrochlorothiazide (12.5 to 25 mg daily) as monotherapy in black patients with mild to moderate hypertension. Am J Hypertens 1995;8:1046 –1050.
15.
Elliott HL, Meredith PA: Methodological considerations in calculation of the trough:peak ratio. J Hypertens 1994;12(suppl 8):S3–S7.
1999;12:528 –531
Low Dose Bendrofluazide (1.25 mg) Effectively Lowers Blood Pressure Over 24 h Results of a Randomized, Double-Blind, Placebo-Controlled Crossover Study M. Ivan Wiggam, Patrick M. Bell, Brian Sheridan, Anona Walmsley, and A. Brew Atkinson
Previous studies indicate that low dose bendrofluazide (1.25 mg/day) has no deleterious effect on insulin sensitivity in contrast to conventional doses. To evaluate the antihypertensive effect of 1.25 mg bendrofluazide across 24 h, we studied 12 subjects in a randomized, double blind, cross-over trial, comprising 8 weeks of either 1.25 mg/day bendrofluazide or placebo. Twenty-four-hour blood pressure averages were significantly lower after bendrofluazide compared with placebo (systolic
I
n the treatment of hypertension the role of therapy is not only to lower blood pressure but also to reduce overall cardiovascular risk.1,2 Given evidence linking insulin resistance and hyperinsulinemia to atheromatous disease,3,4 it has been argued that antihypertensive agents with neutral or beneficial effects on insulin resistance should be used in preference to those with known harmful effects.2 Since their introduction in 1957, thiazide diuretics have remained popular as effective, well tolerated once-daily therapy for arterial hypertension. In large prospective studies of mild hypertension, they have
From the Sir George E. Clark Metabolic Unit (MIW, PMB, ABA), and the Regional Endocrine Laboratory, Royal Victoria Hospital (BS), Belfast, and Lisburn Health Centre (AW), Lisburn, County Antrim, Northern Ireland. During the course of these studies Dr. Wiggam was the recipient of a Royal Victoria Hospital Research Fellowship. Address correspondence and reprint requests to Professor A. B. Atkinson, Sir George E. Clark Metabolic Unit, Royal Victoria Hospital, Belfast, BT12 6BA, Northern Ireland.
© 1999 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
125 6 4 v 136 6 3 mm Hg, P < .005; diastolic: 78 6 2 v 85 6 2 mm Hg, P < .01). Trough:peak ratios were 0.67 6 0.07 for systolic and 0.72 6 0.15 for diastolic blood pressure reduction. In conclusion, 1.25 mg bendrofluazide daily produced a useful antihypertensive effect across the full 24-h period. Am J Hypertens 1999;12:528 –531 © 1999 American Journal of Hypertension, Ltd. KEY WORDS:
Thiazide diuretics, ambulatory blood pressure monitoring, hypertension, bendrofluazide.
produced consistent benefit, particularly in reducing the risk of stroke.5 However the reduction in excess risk of coronary heart disease has been less than expected.5 One possible explanation for this is that the benefits of blood pressure reduction were offset by adverse effects of therapy on lipid profiles, glucose tolerance, and insulin sensitivity. It is now well recognized that thiazide-induced effects on plasma glucose, lipids, and lipoproteins are dose-dependent and can be minimized by using lower doses.6 We have previously shown that low dose bendrofluazide (1.25 mg daily) has no deleterious effects on peripheral or hepatic insulin sensitivity, in contrast to conventional dose bendrofluazide (5 mg daily), in patients with essential hypertension7 and in patients with hypertension and type 2 diabetes mellitus.8 More recently we have also found the intermediate dose of 2.5 mg daily to adversely affect insulin action in hypertensive patients with type 2 diabetes.9 Before low dose bendrofluazide (1.25 mg daily) can be recommended for routine clinical use, it is neces0895-7061/99/$20.00 PII S0895-7061(98)00268-4
AJH–MAY 1999 –VOL. 12, NO. 5
ANTIHYPERTENSIVE EFFICACY OF LOW DOSE BENDROFLUAZIDE
sary to consider its efficacy. Although previous studies using clinic blood pressure measurements at the end of dose interval suggest that the hypotensive effect of low dose bendrofluazide is similar to that of higher doses,6 – 8 no studies have assessed 24-h blood pressure control with low dose bendrofluazide and its trough:peak ratio has not been determined. Homogenous 24-h blood pressure control is now considered an important goal of therapy, and determination of the trough:peak ratio is required by the US Food and Drug Administration for all new antihypertensive agents. To provide this information for low dose bendrofluazide (1.25 mg daily) we have conducted a randomized, placebo-controlled crossover trial using ambulatory blood pressure monitoring under standardized conditions. SUBJECTS AND METHODS Subjects White hypertensive patients of western European origin, aged ,65 years, were recruited from general practice. Exclusion criteria were as follows: cardiac, hepatic, or renal disease; diabetes mellitus; drug therapy that might affect blood pressure; secondary hypertension and clinic diastolic blood pressure outside the range of 95–110 mm Hg after a 6-week placebo run-in. All patients gave written informed consent, and the protocol was approved by the Ethics Committee of the Queen’s University of Belfast. Study Design A randomized, double blind crossover design was employed. Antihypertensive therapy was discontinued and placebo substituted during a 6 week run-in. At the end of this period only those patients with clinic diastolic blood pressure of $ 95 mm Hg were eligible to continue. Patients were randomized to receive either placebo or bendrofluazide 1.25 mg daily for an 8-week period. Patients then proceeded to a 6-week placebo washout, after which they crossed over to receive the alternative, randomly allocated bendrofluazide or placebo for a further 8 weeks. Assessment Throughout the trial patients were seen by the same investigator, during and at the end of each treatment period. Patients attended while fasting, before taking their study medication. Clinic blood pressure was measured using a Hawksley random zero sphygmomanometer and the mean of three readings was used. At each visit venous blood was drawn for measurement of plasma glucose, serum urea, creatinine, electrolytes, glycated hemoglobin, hemoglobin, and lipid concentrations. At baseline (after the 6-week placebo run-in) and at the end of the two 8-week treatment periods, 24-h ambulatory blood pressure measurements were performed using the Tycos QuietTrak ambulatory moni-
529
tor (Welch Allyn, Skaneatles Falls, NY)10 under standardized conditions. Patients were admitted to the hospital on the evening before assessment and halfhourly blood pressure recordings commenced to allow familiarization with the equipment. At set-up, simultaneous measurements were obtained by the monitor and an investigator using a T-tube connected to a mercury sphygmomanometer. Device inaccuracy was excluded by ensuring that consecutive systolic and diastolic readings obtained by the device differed by no more than 5 mm Hg from those obtained by the investigator. Study medication was administered by the nursing staff at 8 am on the morning after admission and half-hourly blood pressure monitoring was continued for a further 24 h. After each recording session, ambulatory blood pressure data were down-loaded to a personal computer. A software package (QTrak Version 1.0, Tycos Instruments) was used to edit the data based on predetermined criteria for the identification of erratic readings. On average, 97% of the data for each patient was available for further analysis after editing. Data for the 24 h of recording after drug administration were analyzed. Night blood pressure was taken as the recordings from midnight to 6 am, which corresponds to the normal rest period on the hospital ward. Hourly blood pressure averages were determined for individual patients and the trough and peak of the antihypertensive effect computed as the difference between blood pressure profiles on placebo and active treatment.11 For peak effect the hour with maximum blood pressure change between 2 and 8 h after drug administration was selected. The drug effect during this selected hour was averaged with that of the adjacent hour (within the 2 to 8 h interval) in which the effect was most evident.11 Trough response was derived by averaging mean blood pressure changes from the final 4 h of the 24-h profile. Individual trough:peak ratios were calculated for responders (peak effect . 10 mm Hg) and the mean ratio in responders was determined.11 Trough: peak ratio for the group as a whole was also calculated by an alternative method in which the mean of individual troughs is divided by the mean of individual peaks for the group.12 Statistical Aspects The number of subjects provided 95% power to detect a 7 mm Hg change in average 24-h diastolic blood pressure at the 5% significance level. Statistical analysis was performed using the Hills and Armitage method as previously described.7 This method enables comparisons of the effects of bendrofluazide and placebo to be adjusted for any period effects. No carry-over effect was detected for any variable measured and there was therefore no necessity to analyze any variables as a parallel study.
530
AJH–MAY 1999 –VOL. 12, NO. 5
WIGGAM ET AL
Results are expressed as means and standard errors of the mean (SEM). Significance was taken as P , .05. RESULTS Of 15 patients enlisted for the study, 13 fulfilled the entry criteria (in one subject the diastolic blood pressure exceeded a predefined limit of 110 mm Hg; the other was found to have proteinuria and was excluded). One additional patient withdrew during the first treatment period for reasons unconnected with the study. The 12 remaining patients completed the protocol (three male, nine female; mean age 53 6 3) years; body mass index 31.5 kg/m2). Patient compliance was good, with . 95% of the study medication being consumed by all participants. Mean 24-h systolic pressure after bendrofluazide was 125 6 4 mm Hg, compared with 138 6 5 mm Hg at baseline (P , 0.05) and 136 6 3 mm Hg after placebo (P , .005). Mean 24-h diastolic pressure after bendrofluazide was 78 6 2 mm Hg, compared with 86 6 3 mm Hg at baseline (P , .05) and 85 6 2 mm Hg after placebo (P , 0.01). Both day and night blood pressure averages were significantly lower after bendrofluazide compared with placebo. Systolic and diastolic blood pressure profiles across the 24-h period showed homogenous blood pressure reduction with low dose bendrofluazide, as shown by Figure 1. Trough:peak ratios in responders averaged 0.67 6 0.07 for systolic blood pressure and 0.72 6 0.15 for diastolic blood pressure (peak blood pressure response $ 10 mm Hg; n 5 9 for systolic blood pressure, n 5 7 for diastolic blood pressure). The trough:peak ratio calculated from the mean of individual trough and peak effects from the whole group was 0.57 for both systolic and diastolic blood pressure. Serum potassium was marginally lower after bendrofluazide compared with placebo (3.8 6 0.1 v 4.1 6 0.1 mmol/L, P , .05), although in no case did the level fall below 3.4 mmol/L. Bendrofluazide had no effect on serum urea and creatinine levels. Serum urate levels were slightly higher after bendrofluazide (0.37 6 0.03 v 0.33 6 0.02 mmol/L, P , .005), although no subject developed clinical gout. No significant changes in fasting glucose or glycated hemoglobin concentrations were found. Total cholesterol levels were slightly lower after bendrofluazide compared with placebo (5.3 6 0.02 v 5.5 6 0.03 mmol/L, P , .005). DISCUSSION Increasingly, in the treatment of essential hypertension, emphasis is being placed on overall cardiovascular risk reduction as well as on blood pressure control.1,2 Choice of antihypertensive agent is influenced by known effects on various parameters including insulin sensitivity, which often clusters with a number
FIGURE 1. Systolic (SBP) and diastolic (DBP) blood pressure profiles after placebo and 1.25 mg bendrofluazide (2-hourly averages) demonstrate uniform blood pressure reduction throughout the 24-h interval after drug administration (8 am in all cases).
of vascular risk factors and may play a central role in the process of atherogenesis.3,4,13 Conventional doses of thiazide diuretic adversely affect insulin sensitivity,7–9 whereas low dose bendrofluazide (1.25 mg daily) has been shown by glucose clamp methodology to have no harmful effect on either peripheral or hepatic insulin action.7,8 In this double blind, placebo-controlled, crossover study we have demonstrated that once-daily bendrofluazide 1.25 mg lowers average 24-h ambulatory blood pressure by 11/7 mm Hg, a reduction that is comparable to that reported with other well accepted antihypertensive agents. Trough:peak ratios calculated by alternative methods indicate a sustained antihypertensive effect throughout the 24-h dose interval. One previous study reported a significant reduction in 24-h blood pressure averages with hydrochlorothiazide 12.5 mg daily with a trough:peak ratio of 0.57.14 This study, which was limited to black South African patients, did not have a randomized placebo control and relied on comparisons against a baseline placebo period.14 By contrast, the present study used a randomized, double blind, placebo-controlled design, and included only white subjects. To the best of our knowledge, the present study is the first to character-
AJH–MAY 1999 –VOL. 12, NO. 5
ANTIHYPERTENSIVE EFFICACY OF LOW DOSE BENDROFLUAZIDE
ize the 24-h antihypertensive effect of bendrofluazide 1.25 mg—the only low dose thiazide the neutrality of which, in relation to insulin resistance, has been verified by glucose clamp methodology.7,8 In addition to a randomized placebo period, the present study involved ambulatory blood pressure recording under carefully controlled conditions, to maximize reproducibility and increase the precision of placebo-drug comparisons. These design features have previously been recommended for the accurate determination of trough:peak ratios.15 Although the US Food and Drug Administration has recommended for several years that new antihypertensive agents have a trough:peak ratio of $ 50%, there is a lack of standardized guidelines as to how trough:peak ratios should be calculated. In a large study, Omboni et al specifically addressed a number of methodological issues concerning the calculation of trough:peak ratios and suggested that ratios should ideally be calculated in individual patients but be limited to those who respond to treatment.11 It is argued that avoidance of nonresponders removes values that are often erratic and have no pharmacodynamic significance. However, ratios derived from responders only have statistical limitations and should be supported by trough:peak ratios calculated from group means of all the individual troughs and peaks.12 In the present study we have demonstrated acceptable trough:peak ratios with low dose bendrofluazide using both of these methods. In the present study a small, but significant, decrease in serum potassium levels was found in association with low dose bendrofluazide. This was not observed in previous, larger studies involving a longer duration of treatment with 1.25 mg bendrofluazide.6,8,9 In any case the small changes seen in the present study are unlikely to be of biologic significance. In summary, we have shown in a randomized, double blind, placebo-controlled study that 1.25 mg bendrofluazide daily produces an average fall in blood pressure of 11/7 mm Hg across a 24-h period. The trough:peak ratios in responders were excellent at 0.67 for systolic blood pressure reduction and 0.72 for diastolic blood pressure reduction. This low dose of bendrofluazide, which has no adverse effects on peripheral or hepatic glucose metabolism, can now be recommended as a useful agent in the management of essential hypertension, used either alone or in combination. ACKNOWLEDGMENTS We thank Mrs. M. McFarland and Mrs. H. Creighton, Pharmacy Department, Royal Victoria Hospital, for help with
531
randomization and drug dispensing and Dr. C. C. Patterson, Department of Community Medicine and Medical Statistics, the Queen’s University of Belfast, for statistical advice. We are grateful to Mrs. M. Loughran for secretarial assistance.
REFERENCES 1.
Kaplan NM: Antihypertensive therapy to maximally reduce coronary risk. Am Heart J 1993;125:1487–1493.
2.
Reaven GM: Treatment of hypertension: focus on prevention of coronary heart disease. J Clin Endocrinol Metab 1993;76:537–540.
3.
Howard G, O’Leary D, Zaccaro D, et al: Insulin sensitivity and atherosclerosis. Circulation 1996;93:1809–1817.
4.
Despre´s J-P, Lamarche B, Mauriege P, et al: Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:952–957.
5.
Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827– 838.
6.
Carlsen JE, Kober L, Torp-Pedersen C, et al: Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. Br Med J 1990; 300:975–978.
7.
Harper R, Ennis CN, Sheridan B, et al: Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension. Br Med J 1994; 309:226 –230.
8.
Harper R, Ennis CN, Heaney AP, et al: A comparison of the effects of low- and conventional dose thiazide diuretic on insulin action in hypertensive patients with NIDDM. Diabetologia 1995;38:853– 859.
9.
Hunter SJ, Wiggam MI, Ennis CN, et al: Comparison of effects of captopril, used either alone or in combination with a thiazide diuretic, on insulin action in hypertensive type 2 diabetic patients: a double-blind crossover study. Diabet Med (in press).
10.
White WB, Susser W, James GD, et al: Multicenter assessment of the Quiet Trak ambulatory blood pressure recorder according to the 1992 AAMI guidelines. Am J Hypertens 1994;7:509 –514.
11.
Omboni S, Parati G, Zanchetti A, et al: Calculation of trough:peak ratio of antihypertensive treatment from ambulatory blood pressure: methodological aspects. J Hypertens 1995;13:1105–1112.
12.
Zanchetti A, on behalf of the Italian Nifedipine GITS Study Group: Trough:peak ratio of the blood pressure response to dihydropyridine calcium antagonists. J Hypertens 1994;12(suppl 8):S97–S106.
13.
Stout RW: Insulin and atheroma: 20 year perspective. Diabetes Care 1990;13:631– 654.
14.
Skoularigis J, Strugo V, Chopamba A, et al: Low dose hydrochlorothiazide (12.5 to 25 mg daily) as monotherapy in black patients with mild to moderate hypertension. Am J Hypertens 1995;8:1046 –1050.
15.
Elliott HL, Meredith PA: Methodological considerations in calculation of the trough:peak ratio. J Hypertens 1994;12(suppl 8):S3–S7.