Effect of guanfacine on ambulatory. blood pressure and its variability in elderly patients with essential hypertension

Transcription

1 Br. J. clin. Pharmac. (1987), 23, Effect of guanfacine on ambulatory. blood pressure and its variability in elderly patients with essential hypertension A. G. DUPONT, P. VANDERNIEPEN & R. 0. SIX Department of Internal Medicine, University Hospital, Vrije Universiteit Brussel, Laabeeklaan 101, B-1090 Brussels, Belgium 1 The effect of guanfacine (2 mg once daily) on ambulatory blood pressure was studied with the Remler M 2000 recorder in 16 elderly hypertensive patients during a randomized, double-blind, placebo-controlled, balanced, cross-over study. 2 Guanfacine significantly reduced heart rate and systolic and diastolic ambulatory blood pressure. The antihypertensive effect was maintained over the whole recording period. 3 Systolic and diastolic blood pressure variability was not changed by guanfacine, neither when defined as standard deviation or variation coefficient of the mean, nor when defined as the range between the highest and lowest ambulatory blood pressure, suggesting that blood pressure variability is unrelated to sympathetic nervous system activity. Keywords guanfacine elderly hypertensive patients ambulatory blood pressure Introduction There is increasing interest in the use of noninvasive ambulatory blood pressure monitoring for the accurate assessment of blood pressure characteristics and for the evaluation of antihypertensive treatment (Brunner etal., 1985a,b; Mancia et al., 1985; Sleight, 1985). Ambulatory blood pressures are generally lower than the office pressures (Brunner et al., 1985a; Sleight, 1985), especially in the elderly (Rowlands et al., 1983), and are better predictors of cardiovascular risk (Sokolow et al., 1966; Perloff et al., 1983; Brunner et al., 1985b). The Remler M 2000 Portometer is a semiautomatic portable recorder which is reliable and accurate for the non-invasive measurement of daytime ambulatory blood pressure (Fitzgerald et al., 1982; Gould et al., 1984; Brunner et al., 1985a). Furthermore this device allows one to obtain a measure of the overall arterial pressure variability during the waking hours (Horan et al., 1981; Clement et al., 1983; Jacot-des-Combes et al., 1984). The latter is important in view of the fact that the magnitude of the blood pressure variability bears a positive relationship with the target organ damage of hypertension (Parati et al., 1985) and that it may represent one of the factors involved in the development of hypertension-related cardiovascular morbidity and mortality (Mancia et al., 1985). We used the Remler M2000 Portometer to evaluate the effects of chronic administration of guanfacine, a central inhibitor of sympathetic nervous tone (Scholtysik, 1980; Reid et al., 1983) in elderly hypertensive patients. The purposes of this study were first, to evaluate the efficacy and tolerability of guanfacine treatment in elderly hypertensives, and, second, to assess whether central inhibition of sympathetic tone by guanfacine, would reduce blood pressure variability. Methods Patients Twenty-eight elderly hypertensive patients con- Correspondence: Dr Alain G. Dupont, Department of Internal Medicine, AZ V.U.B., Laarbeeklaan 101, B-1090 Brussels, Belgium 397

2 398 A. G. Dupont, P. Vanderniepen & R. 0. Six sidered to have mild to moderate hypertension on the basis of at least three 'office' blood pressure readings (supine diastolic blood pressure between 95 and 115 mm Hg) were recruited. Twelve of them had to be excluded because they appeared to be normotensive (blood pressures lower than 140/90 mm Hg) when the first ambulatory blood pressure recordings were decoded. The remaining 16 patients had average ambulatory blood pressures between 95 and 115 mm Hg, and took part in the study. Eight were female and eight were male; their mean age was 67.9 years. None of them had secondary hypertension or evidence of organ damage due to hypertension; patients with renal failure, with a history of cerebrovascular accident or myocardial infarction in the last 6 months, with A-V conduction abnormalities or with diabetes mellitus necessitating therapy with insulin or oral antidiabetics, were ineligible for entry. All previous antihypertensive treatment was withdrawn at least 3 weeks before entering the study. Prior to entry into the study, all patients had a full clinical history recorded and underwent clinical and laboratory examinations. The study protocol was approved by the local Hospital Ethics Committee and informed consent was obtained in each case. Study design The study was of randomized, double-blind, placebo-controlled, balanced, cross-over design. Both treatment phases lasted 4 weeks and were separated by a 3 week single-blind placebo washout period. Either guanfacine 2 mg or placebo were administered at h as a single daily dose. Ambulatory blood pressure monitoring was performed at the beginning and at the end of each treatment phase. The patients attended the hypertension clinic every 2 weeks, for the measurement of supine and standing 'office' blood pressure, using a standard sphygmomanometer, at h. Methodology Office blood pressure was always measured in the same room, by the same observer. Supine office blood pressure was defined as the average of three readings taken after 10 min of supine rest, and standing blood pressure as the average of three readings after 2 min standing. (Korotkoff phase V was accepted as the diastolic level). The semi-automatic Remler M 2000 portometer was used for non-invasive ambulatory blood pressure monitoring. The details of the design of the apparatus have been published previously (Fitzgerald et al., 1982, Gould et al., 1984). The patients left the hospital after they were fitted with the device and they were instructed to inflate the cuff every 30 min between h and h. The choice of interval of 30 min has been validated by comparison with the continuous beat-to-beat intra-arterial recording (Di Rienzo et al., 1983; Brunner et al., 1985a). The rate of deflation of the cuff was set at 10 mm Hg per period of 1.5 s. The tapes were then evaluated using a Remler M 3000 decoding unit and systolic and diastolic blood pressure (Korotkoff V) were defined for each pressure recording. Calculations and definitions All systolic and diastolic ambulatory blood pressures measured during one recording session were averaged. Blood pressure variability was defined as the standard deviation (s.d.) or as the variation coefficient (VC, obtained by dividing the standard deviation by the mean of the blood pressures), or as the range between the highest and lowest ambulatory blood pressure. Blood pressure was considered 'normalised' when diastolic ambulatory blood pressure dropped to below 90 mm Hg; a lowering of > 10 mm Hg was considered a 'good response'. Analysis of results All results are expressed as mean ± s.e. mean. Values obtained at the end of the active treatment period were compared with those obtained at the end of the placebo period using the Wilcoxon matched-pairs signed-rank test. A significant difference was accepted at a two-tailed P <0.05. Results Baseline supine and standing office blood pressure were ± 5.3/104.3 ± 1.9 and ± 5.6/107.3 ± 1.6 mm Hg respectively; baseline ambulatory blood pressure was ± 3.0/ mm Hg. The office blood pressure and heart rate responses to guanfacine are given in Table 1. Guanfacine significantly reduced both supine and standing systolic and diastolic blood pressure, without inducing orthostatic hypotension. Guanfacine did not cause bradycardia in any of the patients, although it induced a small but statistically significant reduction in heart rate. When the data of the group of 16 patients were considered, there was a significant decrease of

3 Guanfacine elderly hypertensive patients Table 1 Office blood pressures and heart rate at the end of both treatment phases (mean ± s.e. mean, *P < 0.01) Placebo Guanfacine Supine office BP (mm Hg) ± 4.6/103.8 ± ± 4.6*/91.3 ± 1.8* Standing office BP (mm Hg) ± 5.0/106.4 ± ± 5.5*/92.1 ± 2.4* Supine heart rate (beats min-1) 78.6 ± ± 1.5* Standing heart rate (beats min-1) 82.3 ± ± 1.5* 399 the average systolic and diastolic ambulatory blood pressure after 4 weeks of treatment with guanfacine as compared with the corresponding values obtained after 4 weeks of placebo (Table 2). Blood pressure was normalised (diastolic ambulatory blood pressure < 90 mm Hg) by guanfacine in 8/16 patients and a good response (fall of 3 10 mm Hg) was obtained in 13 patients. As shown in Figure 1, both systolic and diastolic ambulatory blood pressure were reduced during the 8 h recording period. No statistically significant difference in blood pressure variability could be shown between placebo and guanfacine treatment, when defined as either the standard deviation of the mean, as the variation coefficient or as the range between the highest and lowest blood pressure in individual recording sessions. One patient complained of headache during the placebo-period. During treatment with Table 2 Ambulatory blood pressure and its variability defined as standard deviation (s.d.) or as the variation coefficient (VC) of the average of systolic and diastolic ambulatory blood pressures, or as the range between the highest and the lowest blood pressure (mean ± s.e. mean*, P < 0.01) Placebo Guanfacine Ambulatory blood pressure (mm Hg) systolic ± ± 4.4* diastolic ± ± 2.0* Systolic variability s.d. (mm Hg) 13.7 ± ± 1.7 VC (%) 8.0 ± ± 1.3 Range (mm Hg) 47.2 ± ± 3.3 Diastolic variability s.d. (mm Hg) 6.7 ± ± 0.5 VC (%) 6.5 ± ± 2.4 Range (mm Hg) 23.6 ± ± 1.4 l 80 a /ff-_ l 75 A o - I E E a) 0. C,) 170 l 145L- 165 Co , m Time of day (h) Figure 1 Ambulatory blood pressures during the 8 h registration period at the end of the placebo (0) and guanfacine (A) treatment period.

4 400 A. G. Dupont, P. Vanderniepen & R. 0. Six guanfacine, one patient complained of severe dryness of mouth, accompanied by sedation, decreased libido and heavy legs. In nine other patients, mild transitory dryness of mouth was noted at the beginning of the guanfacine administration. This complaint subsequently resolved, within 2-3 weeks. Discussion The results of the present study indicate that 2 mg guanfacine given once daily in the evening is well tolerated and effective in the treatment of mild to moderate hypertension in elderly patients. The blood pressure lowering effect was confirmed by the non-invasive measurement of ambulatory blood pressure using a semi-automatic device (Remler M 2000). It has become evident in recent years that this method is more reliable for the evaluation of antihypertensive efficacy of drugs than the conventional measurement of office blood pressures (Brunner et al., 1985a). In fact, the use of this method in the present study permitted us to exclude 12 normotensive patients who would otherwise have been erroneously considered as true hypertensives and included in the study. This disparity between casual and ambulatory blood pressures is a generally recognized phenomenon (Waeber et al., 1984), which appears to be particularly important in the elderly (Rowlands et al., 1983; Dupont et al., 1985). The Remler recording furthermore allowed us to demonstrate that the hypotensive effect was malntained throughout the recording period. This indicates that guanfacine, in a once daily administration, is capable of decreasing blood pressure over a period of at least 21 h, which is in agreement with its long plasma elimination halflife (Kiechel, 1980) and confirms the findings of Mann et al. (1980) in younger patients. Side effects observed in this study were similar to those reported earlier (Jerie, 1983); they were usually very mild and disappeared within 2-3 weeks. We feel that the frequency of side effects would even be lower if, in these elderly patients, a starting dose of 1 mg were used. Except for one patient, all patients, continued on treatment with guanfacine (2 mg once daily) after terminating the study. In those patients in whom blood pressure was not normalised by guanfacine alone, blood pressure control could be achieved by adding a diuretic. Blood pressure variability has been reported to be increased in the elderly (Drayer et al., 1982). Furthermore, catecholamine levels, particularly of noradrenaline, are reportedly high in elderly subjects (Lake et al., 1977, Sever et al., 1977, Sowers et al., 1983). As there is evidence of a relationship between the level of sympathetic activity and blood pressure variability (Floras & Sleight, 1982), it is tempting to speculate that the increased blood pressure variability in the elderly could be related to the higher plasma noradrenaline levels. The results of the present study, however, do not favour such an hypothesis: guanfacine, which acts through stimulation of central a2-adrenoceptors to reduce sympathetic tone (Reid et al., 1983, Sorkin & Heel, 1986), did not reduce blood pressure variability (neither when defined as standard deviation or variation coefficient of the mean, nor when defined as the range between the highest and lowest ambulatory blood pressure). This suggests that, at least in this age group, blood pressure variability is unrelated to the activity of the sympathetic nervous system. The increased blood pressure variability in the elderly are probably accounted for by vascular phenomena, such as stiffness of the major arteries and/or the decline in baroreceptor sensitivity (Gribbon et al., 1971; Watson et al., 1980). We are indebted to Mrs Mariette Doclo for secretarial help. Sandoz Belgium is acknowledged for providing guanfacine and for financial support. References Brunner, H. R., Waeber, B. & Nussberger, J. (1985a). Clinical use of non-invasive ambulatory blood pressure recording. J. Hypertension, 3 (suppl. 2), Brunner, H. R., Waeber, B. & Nussberger, J. (1985b). Blood pressure recording in the ambulatory patient and evaluation of risk. Clin. Sci., 68, Clement, D. L., Cardon, E., Castro, M., De Pue, N., Packet, L. & Van Maele, G. 0. (1983). Effect of metoprolol and of guanfacine on ambulatory blood pressure and its variations. Br. J. clin. Pharmac., 15, 471S-478S. Conway, J., Boon, N., Davies, C., Vann Jones, J. & Sleight, P. (1984). Neural and humoral mechanisms involved in blood pressure variability. J. Hypertension, 2, Di Rienzo, M., Grassi, G., Pedotti, A. & Mancia, G. (1983). Continuous versus intermittent blood pressure measurements in estimating 24-hour average blood pressure. Hypertension, 5, Drayer, J. I. M., Weber, M. A., De Young, J. L. & Wyle, F. A. (1982). Circadian blood pressure pattern of age. Am. J. Med., 73, Dupont, A. G., Vanderniepen, P., Finne, E. & Six,

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