The treatment of benign prostatic hyperplasia with alpha blockers in men over the age of 80 years

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1 British Journal of Urology (1997), 8, The treatment of benign prostatic hyperplasia with alpha blockers in men over the age of 8 years S.A. KAPLAN, A.E. TE, E. IKEGUCHI and R.P. SANTAROSA Department of Urology, Columbia University, New York, NY, USA Objective To determine the safety and ebcacy of alpha and terazosin (+3.2 ml/s). The American Urological blockade with doxazosin and terazosin in men over Association symptom score improved significantly the age of 8 years with symptomatic benign prostatic (P<.1) with both alpha blockers after 3 months of hyperplasia (BPH). treatment and ebcacy was maintained at 6 months. Patients and methods Thirty-six men (mean age 83.6 There were small, non-significant decreases in blood years, sd 5.6, range 8-96) received either doxazosin pressure in patients receiving doxazosin or terazosin, 4 mg (11 men) or 8 mg (1 men), or terazosin 5 mg but no dicerences between patients who were normotensive (five men) or 1 mg (1 men), once daily at night. at baseline and those whose blood pressure was Twenty-eight men (78%) were on other anti- controlled by other anti-hypertensive drugs. hypertensive medication; the type and dosage were Conclusion These results suggest that alpha blockade not changed during the study. EBcacy and safety were with either doxazosin or terazosin is well tolerated assessed using measurements of peak urinary flow and ecective in older men with symptomatic BPH. rate, symptom scores and the incidence of adverse Furthermore, patients on concomitant antihypertensive events. medication need no alteration of their Results Of the 36 men, 33 (92%) remained on study therapeutic regimen before the initiation of alpha medication at 6 months; the remaining three (8%) blockade for BPH. discontinued because of asthenia. After 3 months of Keywords Benign prostatic hyperplasia, doxazosin, terazosin, treatment, the peak urinary flow rate increased significantly anti-hypertensive (P<.8) for both doxazosin (+3.7 ml/s) appropriate form of treatment in consultation with his Introduction physician [2]. However, particular considerations apply The number of men diagnosed with BPH is increasing in the choice of treatment for very elderly patients. as the world population ages; life expectancy is likely to Although TURP is still considered the most ecective exceed 8 years in many developed countries by the end treatment, it may not be the best choice for most very of this century. By their eighth decade, almost 9% of elderly patients, who generally tolerate hospitalization men have histological BPH [1] and an estimated quarter and anaesthesia less well than younger patients. The have symptoms troublesome enough to require therapy risk of post-operative morbidity and mortality after TURP [2]. In the past, older men have been reluctant to seek is high in men aged over 8 years [5,6]. Surgery will be medical help for prostatic symptoms, mainly because imperative for some elderly men who present with they fear surgery, preferring instead to adapt their lifestyle complications from BPH, but a trial of medical therapy to compensate [3,4]. This situation is now chang- may be a more suitable option for many of the others. ing, with the greater public awareness of ecective nonsurgical Pharmacological therapy with selective alpha-1 block- treatments. Older men have increased expec- ers has become a well established treatment modality tations of quality of life and are less willing to tolerate for BPH. Although alpha blockade is well tolerated by bothersome urinary symptoms; physicians are likely to most men with BPH, up to 1% of patients in clinical see more men in their 8s seeking help. studies withdraw from treatment because of side-ecects BPH can be treated ecectively with surgical or pharma- [7]. The type of side-ecects most commonly associated cological therapies. Clinical practice guidelines for BPH with alpha-1 blockers, i.e. dizziness, asthenia and pos- recommend that each patient should decide the most tural symptoms, are of special concern in elderly patients who are more prone to falls and fractures. Elderly Accepted for publication 29 July 1997 patients are likely to have concomitant diagnoses and 1997 British Journal of Urology 875

2 876 S.A. KAPLAN et al. may be taking many dicerent prescribed and over-theand Table 1 The number of patients recruited and evaluable at both 3 counter medications, thus increasing the risk of drug 6 months interactions and side-ecects. Furthermore, the physiological consequences of ageing, such as impaired renal and hepatic function, may alter the pharmacokinetics of Dose (mg) drugs. It is therefore vitally important to establish the safety and tolerance of alpha-1 blockers for the treatment Recruited of BPH in elderly men. Thus, the objective of this study Evaluable was to determine the ebcacy and safety of two alpha-1 blockers, doxazosin and terazosin, in men aged over 8 years with symptomatic BPH. Withdrawn (adverse event) (P<.1, Fig. 1b) after 3 months of treatment with Patients and methods doxazosin or terazosin; the ebcacy was maintained at 6 months. The reductions in standing blood pressure after Thirty-six men (mean age 83.6 years, sd 5.6, range 3 and 6 months were small and non-significant with 8 96) with symptomatic BPH were enrolled in an both alpha blockers (Fig. 2a) and overall, there were no open, prospective study; patients were not randomized apparent dicerences in blood pressure changes between and received either doxazosin (titrated to 4 or 8 mg) or patients who were normotensive and those treated with terazosin (titrated to 5 or 1 mg) once daily at night. anti-hypertensives (Fig. 2b). The first 15 patients were started on terazosin (five on Eleven patients (31%) experienced adverse events, 5 mg, 1 on 1 mg) and the following 21 on doxazosin including asthenia (five), dizziness (three), headache (11 on 4 mg, 1 on 8 mg). At the beginning of recruit- (two) and rhinitis (one). Of these eleven, three patients ment, terazosin was the primary alpha blocker used by discontinued treatment (one on doxazosin 4 mg, one the investigators. After approval by the Food and Drug doxazosin 8 mg and one terazosin 5 mg); all three experi- Administration, doxazosin was used in the subsequent enced asthenia (Table 1). group. Patients were excluded if they had a history of prostate cancer, neurogenic bladder or urethral stricture. The type and dosage of any concurrent antihypertensives were not changed during the study. Most ** * 14 a ** * 12 patients (28/36, 78%) were taking a combination of 1 concurrent anti-hypertensives at baseline, i.e. ACE inhibitor and calcium-channel blocker (16), diuretic and calcium-channel blocker (five), beta blocker and calciumchannel blocker (four), or diuretic and ACE inhibitor (three). Patients were not on alpha blockers for hypertension nor were they ever treated by alpha blockade in 2 the past. EBcacy was assessed at baseline and after 3 and 6 months of treatment by measurements of peak urinary 2 b flow rate (Q ) and completion of the AUA symptom max score. Safety was assessed as the change in sitting and 15 standing blood pressure after 3 and 6 months of treatment, and side-ecects leading to withdrawal of medication. The data for both treatment groups (dosages) * 1 * * * were combined for the statistical analysis, with paired t- tests used to assess changes from baseline and twosample 5 t-tests for the dicerences between patient groups. Results Q max (ml/s) AUA score Fig. 1. The mean, a, Q and, b, AUA symptom severity score at Of the 36 men enrolled, 33 (92%) remained on study max baseline (dark green) and after 3 (light green) and 6 (light red) medication and were evaluable at 3 and 6 months months of treatment with doxazosin (19 men) or terazosin (14 (Table 1). There were significant improvements in Q max men). The AUA score ranges from to 35 with higher scores (P<.8, Fig. 1a) and AUA symptom severity score indicating greater severity.

3 Change on blood pressure (mmhg) Blood pressure (mmhg) months Normotensive 6 months 3 months 6 months Concurrent antihypertensives Fig. 2. The mean change in standing blood pressure, a, after 3 and 6 months of treatment with doxazosin (19 men) or terazosin (14 men) (green, systolic; red, diastolic) and, b, at baseline (green) and after 3 months (red) of treatment with doxazosin and terazosin in patients who were normotensive or taking concurrent antihypertensive drugs. Discussion ALPHA BLOCKERS FOR BPH IN MEN OVER EIGHTY 877 alpha-1 blockers [13,14]. Analysis of data from five double-blind, placebo-controlled trials has shown that the safety profile of doxazosin is similar in older and younger patients, and that the incidence of vasodilatoryrelated adverse events is low [11]. In contrast, data from 13 clinical studies involving terazosin indicated that vasodilatory-related adverse events such as postural hypotension, dizziness and syncope tend to occur more frequently in older patients [12]. Thus, the administration of doxazosin may be preferable in elderly patients. Evidence of an increased risk for hypertension among men with BPH has recently been reported [15]. It is clear that a large proportion of elderly men sucer from both BPH and hypertension [16]. In the present study, patients treated with concurrent anti-hypertensives experienced clinically insignificant changes in blood pressure during 6 months of treatment with either doxazosin or terazosin. However, a recent study [17] highlighted that care should be taken when first administering terazosin and a calcium antagonist; on the initiation of combined terazosin and verapamil therapy, orthostatic hypotension occurred in six of 24 patients. Several studies with more patients have addressed the question of whether it is advisable to add an alpha-1 blocker to existing anti-hypertensive therapy. A combined analysis of six placebo-controlled trials, involving 996 patients, assessed the safety and ebcacy of terazosin for the treatment of BPH and showed that terazosin can be administered safely to both normotensive and hyper- tensive patients with BPH [18]. More recently, results from the Hytrin Community Assessment Trial, a community-based, double-blind, randomized trial involving 284 men, of the treatment of symptomatic BPH with terazosin, have been reported [19]. Among patients treated with terazosin, blood pressure-related adverse events (syncope, dizziness, hypotension, postural hypotension, vertigo) were experienced by 13.1% of men who The overall pharmacokinetic profiles of doxazosin and terazosin are not acected by increasing age of the patient [8,9]. Several studies have assessed the ebcacy and safety of alpha-1 blockers in younger compared with were taking other anti-hypertensives compared with older patients with symptomatic BPH [1 12]. In these 15.2% of those who were not. In a trial involving 63 studies, older patients were defined as those aged 65 men with BPH, Kaplan et al. [2] reported that doxazosin years or more. The beneficial ecects of doxazosin and produced clinically unimportant reductions in blood terazosin on urinary flow rates, and obstructive and pressure in both normotensive patients and in men irritative symptoms, do not appear to be acected by taking other anti-hypertensives concurrently. Evidence age [1,12]. from these studies indicates that therapy with doxazosin Safety is perhaps a more important concern in very or terazosin can be introduced for the treatment of BPH elderly patients. The clinical improvement with some in older patients whose blood pressure is already controlled alpha-1 blockers, e.g. terazosin, in patients with BPH is by concomitant anti-hypertensives. often ocset by adverse events, including orthostatic In the present study, both doxazosin and terazosin ecects such as first-dose and postural hypotension [13]. were administered once-daily at night. Evening adminis- However, few adverse events are associated with the tration is advisable for most alpha-1 blockers to minimize newer agents with longer half-lives, e.g. doxazosin, the potential for adverse events such as dizziness, hypo- which has a half-life of 22 h, the longest of the available tension and syncope. However, with doxazosin, the time

4 878 S.A. KAPLAN et al. of dosing does not appear to influence its ebcacy and prostatectomy: immediate and post-operative compli- safety in patients with BPH, suggesting that there is no cations. J Urol 1989; 141: need to restrict administration of doxazosin to the eve- 6 Wyatt MG, Stower MJ, Smith PJB, Roberts JBM. ning [21]. There have been no other reported studies Prostatectomy in the over 8-year-old. Br J Urol 1989; 64: evaluating the relative ecects of morning and evening 7 Kirby RS. a-blockers in BPH: Clinical aspects. In Cockett dosing regimens of long-acting alpha-1 blockers in ATK, Khoury S, Aso Y et al. eds, Proceedings of the 3rd patients with BPH, although Lepor et al. [22] have International Consultation on Benign Prostatic Hyperplasia suggested that terazosin-induced fatigue may be reduced (BPH). Jersey: Scientific Communication International Ltd, by administering the drug at bedtime in such patients. 1996: Most recently, the potential role of more prostate- 8 Vincent J, Meredith PA, Elliott HL, Reid JL. The pharmacokinetics selective agents such as tamsulosin on adverse events of doxazosin in elderly normotensives. Br J Clin associated with terazosin and doxazosin have been Pharmacol 1986; 21: reported. In a 12-week double-blinded study comparing 9 Sennello LT, Sonders RC, Glassman HN, Jordan DC, Luther placebo to.4 mg of tamsulosin, there were no dicerintravenously RR. ECect of age on the pharmacokinetics of orally and administered terazosin. Clin Ther 1988; ences between the treated and placebo groups with 1: 6 respect to dizziness and asthenia. This medication can 1 Kaplan SA. in the older male: ebcacy in treating be given without titration. However, there are no results BPH. Eur Urol 1996; 29 (suppl 1): to date for the safety and ebcacy in a population of men 11 Jardin A, Kirby R, Christensen MM, Janknegt R, over the age of 8 years [23]. Gillenwater J, Fawzy A. is equally well tolerated The interpretation of the results of the present study by older and younger normotensive men. J Urol 1995; is limited because there were few patients and no placebo 153: 273A, 179 group. Nevertheless, there were no selection criteria 12 Wilde MI, Fitton A, Sorkin EM.. A review of its other than having LUTS and being over the age of 8 pharmacodynamic and pharmacokinetic properties and years upon entry into the study. In addition, these data therapeutic potential in benign prostatic hyperplasia. Drugs do not suggest increased ebcacy in men over 8 years Aging 1993; 3: of age; however, they do suggest that alpha blockade 13 Khoury AF, Kaplan NM. Alpha-blocker therapy of hyperten- sion: an unfulfilled promise. JAMA 1991; 266: with either doxazosin or terazosin is ecective and well 14 Lepor H. Nonoperative management of benign prostatic tolerated in such men with symptomatic BPH. Most men hyperplasia. Current pharmacological treatment. J Urol were still taking the alpha-1 blocker at 6 months and 1989; 141: the ebcacy was maintained. 15 Kaplan SA, Santarosa RP, Te AE. The incidence of In conclusion, this study suggests that alpha-1 block- hypertension in a population of men with benign prostatic ade with doxazosin or terazosin would be a good treat- hyperplasia: analysis based on the AUA symptom score ment choice or patients over the age of 8 years and race. Eur Urol 1996; 3 (suppl 2): 99, 332 presenting with uncomplicated symptomatic BPH. 16 Boyle P, Napalkov P. The epidemiology of benign prostatic hyperplasia and observations on concomitant hypertension. Scand J Urol Nephrol 1995; 29: 7 12 References 17 Lenz ML, Pool, JL Laddu, AR Varghese A, Johnston W, Taylor AA. Combined terazosin and verapamil therapy in 1 Berry SJ, CoCey DS, Walsh PC, Ewing LL. The development essential hypertension. Hemodynamic and pharmacokinetic of human benign prostatic hyperplasia with age. J Urol interactions. Am J Hypertens 1995; 8: ; 132: Lowe CL. Safety assessment of terazosin in the treatment 2 McConnell JD, Barry MJ, Bruskewitz RC et al. Benign of patients with symptomatic benign prostatic hyperplasia: Prostatic Hyperplasia: Diagnosis and Treatment. Quick a combined analysis. Urology 1994; 44: Reference Guide for Clinicians. AHCPR Publication 19 Lowe F, Tuttle J, Marks S, Steidle C, Jacobs T, Padley RJ, No Rockville, MD: Agency for Health Care for the HYCAT Investigator Group. Blood pressure ecects Policy and Research, Public Health Service, US Department of men with prostatism concurrently treated with of Health and Human Services. February 1994 anti-hypertensives and terazosin. J Urol 1995; 153: 272A, 3 Tsang KK, Garraway WM. Prostatism and the burden of 176 benign prostatic hyperplasia on elderly men. Age Ageing 2 Kaplan SA, Meade-D Alisera P, Quinones S, Soldo KA. 1994; 23: 36 4 in physiologically and pharmacologically normo- 4 Department of Veterans ACairs cooperative study of tensive men with benign prostatic hyperplasia. Urology transurethral resection for benign prostatic hyperplasia. A 1995; 44: comparison of quality of life with patient reported symptoms 21 Kirby RS, Chapple CR, Sethia K et al. Morning versus and objective findings in men with benign prostatic evening dosing with doxazosin in benign prostatic hyperhyperplasia. J Urol 1993; 15: plasia: ebcacy and safety. Eur Urol 1997; In press 5 Mebust WK, Holtgrewe HL, Cockett ATK. Transurethral 22 Lepor H, Knapp-Moloney G, Sunshine H. A dose titration

5 ALPHA BLOCKERS FOR BPH IN MEN OVER EIGHTY 879 Authors study evaluating terazosin, a selective, once-a-day alpha-1 blocker for the treatment of symptomatic benign prostatic S.A. Kaplan, MD, Herbert Irving Associate Professor and Vice hyperplasia. J Urol 199; 144: Chairman. 23 Schulman CC, Cortvriend J, Lonas U et al. Tamsulosin, the A.E. Te, MD, Assistant Professor of Urology. first prostate-selective a -adrenoreceptor antagonist. 1A E. Ikeguchi, MD, Resident in Urology. Analysis of a multinational, multi-centre, open label study R.P. Santarosa, MD, Neurourology Fellow. assessing the long term ebcacy and safety in patients with Correspondence: Dr S.A. Kaplan, Columbia University, 63 benign prostatic obstruction (symptomatic BPH). Eur Urol West 168th Street, New York, NY 132, USA. 1996; 29: