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Pii: s0022-5347(05)65769-2

Copyright 2001 by AMERICAN UROLOGICAL ASSOCIATION, INC.® LONG-TERM USE OF TAMSULOSIN TO TREAT LOWER URINARY TRACT SYMPTOMS/BENIGN PROSTATIC HYPERPLASIA CLAUDE C. SCHULMAN, TYCHO M. T. W. LOCK, JEAN-MARIE BUZELIN, FRANK BOEMINGHAUS, MEMBERS OF THE EUROPEAN TAMSULOSIN STUDY GROUP From the Erasmus University Hospital, Brussels, Belgium, Academisch Ziekenhuis Utrecht, Utrecht, The Netherlands, Hoˆtel Dieu Nantes, Nantes, France, Urologische Klinik, Neuss, Germany, University Hospital of Wales, Cardiff, United Kingdom, and Pa¨lja¨t-Ha¨me Central Purpose: The long-term efficacy and safety of 0.4 mg. tamsulosin once daily were assessed in patients with lower urinary tract symptoms/benign prostatic hyperplasia treated for up to 4years.
Materials and Methods: A total of 516 patients were enrolled from 2 European open label studies that were extensions of 3 double-blind controlled studies.
Results: Significant improvement in maximum urine flow and total Boyarsky symptom score during the controlled trials was sustained throughout the extension study for up to 4 years inpatients who remained on therapy. The increase in mean maximum urine flow from baseline was1.2 to 2.2 ml. per second (p Ͻ0.001) and it remained 11.5 to 12 ml. per second during followup.
Total Boyarsky symptom score was decreased from baseline by 4.1 to 4.7 points (p Ͻ0.001). Theincidence of treatment responders, defined as a 25% or greater decrease in total symptom score,remained stable throughout the 4-year period. Increasing the dose of tamsulosin from 0.4 to 0.8mg. seemed to have no substantial additional benefit. During the 4 years of treatment 26% ofpatients had side effects that were considered possibly or probably drug related. However, only5% of patients discontinued treatment because of drug related side effects. No clinically signif-icant changes in blood pressure or pulse rate occurred during the study.
Conclusions: Long-term treatment with tamsulosin is safe and well tolerated in patients with lower urinary tract symptoms/benign prostatic hyperplasia. Improved efficacy was sustainedduring 4 years of followup.
KEY WORDS: prostate; prostatic hyperplasia; receptors, adrenergic, alpha-1; urination disorders ␣1-Adrenoceptor antagonists are recommended as the study6 was an extension of 2 randomized, double-blind, pla- main pharmacological treatment for patients with benign cebo controlled phase III studies comparing 0.4 mg. tamsu- prostatic hyperplasia (BPH) presenting with lower urinary losin once daily with placebo.7, 8 The other open label study tract symptoms.1 However, there is a relative paucity of (unpublished data) was an extension of a randomized, long-term data on the maintenance of efficacy of ␣1- double-blind phase III study comparing 0.4 mg. tamsulosin adrenoceptor antagonists. For doxazosin and terazosin long- once daily with 2.5 mg. alfuzosin 3 times daily.9 Patients who term efficacy and safety have been previously shown.2, 3 How- elected to continue tamsulosin treatment after completion of ever, results were based on an interim analysis and the the controlled studies were recruited into the extension study number of patients who were effectively treated for 3 and 4 as soon as possible after the controlled trials. The protocol of the long-term extension studies indicated that open label Several long-term studies with a duration of between 1 and tamsulosin treatment should be continued for at least 1 year 3 years have already confirmed the good efficacy and safety and maximally 4. This final analysis includes patients re- profile of 0.4 mg. tamsulosin once daily.4–6 We present a finalpooled analysis of 2 European open label long-term tamsulo- maining in the study for up to 4 years. The study started in sin studies in which all patients had the option of continuing May 1992 and the last patient completed the study in July for up to 4 years. In addition, the efficacy and safety of 0.8 mg.
1997. Patients from 87 centers in 10 European countries tamsulosin in cases of a less than optimal response to 0.4 mg. tamsulosin were evaluated. To our knowledge this Inclusion and exclusion criteria. Patients who successfully report provides the largest followup of the long-term effi- completed the controlled studies and elected to participate in cacy and safety of an ␣1-adrenoceptor antagonist in a large a long-term open label tamsulosin study were enrolled in the number of patients in which all patients had the option of extension studies. All those who entered the open label ex- tension studies had already fulfilled the inclusion criteria ofthe controlled trials, that is 4 to 12 ml. per second maximum urine flow for a voided volume of 120 ml. or greater, diagnosis This pooled analysis involved 2 European open label stud- of benign prostatic enlargement, total Boyarsky symptom ies of the efficacy and safety of 0.4 mg. tamsulosin once daily score greater than 6 points, a complete set of evaluations for lower urinary tract symptoms/BPH. The first open label available at the clinic visit at the end of the controlled stud-ies, and urinalysis, biochemistry and hematology results Accepted for publication May 25, 2001.
within the normal range. All patients provided gave informed Supported by Yamanouchi Europe B. V.
LONG-TERM TAMSULOSIN USE FOR URINARY TRACT SYMPTOMS consent for participation. All exclusion criteria have been A total of 831 patients were randomized to the controlled Study design and assessments. Patients were treated with studies, of whom 768 (92%) completed the trials. Of these 768 open label 0.4 mg. tamsulosin as a modified release capsule patients 516 (67%) elected participation in the long-term once daily after breakfast. The dose of tamsulosin could be extension studies. Table 1 lists patient demographics and increased to 0.8 mg. from visit 3 (week 26) and thereafter in baseline characteristics, which are in accordance with those the long-term studies if efficacy was not considered optimal normally reported in clinical trials of ␣1-adrenoceptor antag- and no significant side effects probably or possibly related to tamsulosin were reported. Patients were assessed at study en- Table 2 shows the number of patients who withdrew from rollment at visit 1, at 2 weeks at visit 2 and then at 12-week the study before visits 6 (before 1 year), 10 (before 2 years), 14 intervals for the remainder of the study. At each 12-week visit (before 3 years) and 18 (before 4 years). The most common the patient completed the Boyarsky symptom score and free reasons for withdrawal were insufficient therapeutic re- flow studies were performed. At visits 6 at 48 weeks, 10 at 96 sponse, drug related and other side effects and other unspec- weeks, 14 at 144 weeks and 18 at 192 weeks or the last visit ified reasons. At most visits between 1% and 6% of patients when a patient withdrew early from the trial physical exami- withdrew from the study. However, at visit 6 the number of nation and abdominal ultrasound were performed, the investi- patients who withdrew was disproportionately large (77 or gator noted the global efficacy of the medication on a scale of 15%). In the protocol this visit was defined as the point to 0 —worse to 3—much improved and the patient completed a which all patients were treated with tamsulosin with the option of continuing tamsulosin therapy thereafter if study Efficacy assessments. The primary parameters for assess- participation was still desired. After 4 years a third of the ing efficacy were changes in maximum urine flow and total patients remained in the study. Table 3 shows that the dis- Boyarsky symptom score. Other efficacy parameters wereobstructive voiding, irritative filling, and individual symp- continuation rate varied among geographic areas. It was tom scores, quality of life questionnaire and investigator lowest where tamsulosin had not been commercially avail- global assessment of efficacy. In addition, the number of able until July 1997, the date of the last visit in this series, patients with a clinically significant response to tamsulosin such as Belgium and some Nordic countries (Denmark, Nor- was determined, defined as a 25% or greater decrease in total Boyarsky symptom score. Furthermore, patients with a max- Changes in maximum urine flow and total symptom score. imum urine flow response, defined as a 30% or greater, or 3 Figure 1, A shows mean maximum urine flow with time in ml. per second or greater improvement over baseline, were patients treated with tamsulosin for up to 204 weeks (4 years). At baseline mean maximum urine flow was 10.1 ml.
Efficacy was assessed on an intent-to-treat population, in- per second. Already after 4 weeks at the initial assessment in cluding all patients who received at least 1 dose of tamsulosin the placebo controlled studies a maximum increase was in the long-term extension study and who for whom followup achieved that was sustained for up to 4 years of tamsulosin efficacy data were available for at least 1 visit after extension treatment. The increase in mean maximum urine flow from study enrollment. The safety population included all patients baseline was between 1.2 and 2.2 ml. per second (12% and who received at least 1 dose of study medication in the 22%, p Ͻ0.001 versus baseline at each time point). Mean long-term extension study. Safety assessments included maximum urine flow remained predominantly between 11.5 monitoring all reported side effects as well as side effects and 12 ml. per second throughout followup.
considered possibly or probably drug related by the investi- Figure 1, B shows that the mean total Boyarsky symptom gator plus vital signs and laboratory determinations. Within score improved significantly compared with baseline from 6.9 group changes from baseline were assessed using the paired to 9.6 points (p Ͻ0.001) after 4 weeks, which was the first Student t test. All tests were 2-sided with significance con- assessment in the controlled studies. This improvement reached a maximum of 5.4 points after 14 weeks and wassustained for the remainder of tamsulosin treatment (p Ͻ0.001 versus baseline at each time point). The mean de-crease in total symptom score from baseline ranged between TABLE 1. Baseline characteristics of patients in the long-term study 4.1 and 4.7 points (43% and 49%) from 14 weeks of treatmentand thereafter. Irritative filling and obstructive voiding scores were significantly decreased from baseline at all visits.
Changes in maximum urine flow and total symptom score with 0.8 mg. dose. Of the 512 patients in the intent-to-treat population 421 (82%) remained on the 0.4 mg. dose, whereas Mean digital rectal examination gm. prostate in 91 (18%) the dose was increased to 0.8 mg. The group on 0.4 mg. tamsulosin had efficacy comparable to that in the Mean ultrasound ml. prostate vol. Ϯ SD (No. pts.) total population. Mean total symptom score decreased by 4.2 Mean Boyarsky symptom score Ϯ SD (No. pts.) to 4.8 points (44% to 50%), while maximum urine flow in- Mean ml./sec. max. urinary flow Ϯ SD (No. pts.) creased by 1.2 to 2.1 ml. per second (11% to 20%). Meanmaximum urine flow at baseline in patients who changed to TABLE 2. Cumulative number of patients who withdrew before each visit * Some patients withdrew for more than 1 reason.
LONG-TERM TAMSULOSIN USE FOR URINARY TRACT SYMPTOMS TABLE 3. Cumulative number of patients who withdrew before each ment to a maximum of 79% and then remained more or less visit according to geographic area stable for the remainder of the trial. During this period theincidence of symptom score respondents was 74% to 81% (fig.
3, A). The incidence of those considered maximum urine flow respondents was between 30% and 36% (fig. 3, B). When a maximum urine flow response was defined as an increase of 3 ml. per second or greater, the rate was similar (28% to 35%). The mean total quality of life questionnaire score de- creased 6.5 points from a baseline of 20.2 (Ϫ32%, p Ͻ0.001).
Tolerability. During the 4 years of treatment 76% of pa- tients had cumulatively at least 1 side effect, defined as anyevent occurring after the start of treatment or any event thatoccurred before tamsulosin was initiated but had increased 0.8 mg. was lower than in those who remained on 0.4 mg. (9.4 in intensity during treatment. However, only 26% of patients versus 10.3 ml. per second). The mean maximum urine flow had side effects that were considered by the investigator as achieved with 0.4 mg. in these patients was less than in those possibly or probably related to tamsulosin treatment (table who remained on 0.4 mg. (10.2 versus 12.7 ml. per second).
4). The only drug related side effects in at least 3% of patients The additional improvement in maximum urine flow at the were dizziness in 5.8% and abnormal ejaculation in 4.3%.
0.8 mg. dose was minimal (range 0.2 to 0.7 ml. per second, Overall 86 patients (17%) discontinued treatment before 4 years because of side effects (tables 2 and 4). Study with- Total symptom score at baseline was comparable in the drawal was considered possibly or probably drug related by groups (0.8 and 0.4 mg. groups (9.3 and 9.6, respectively).
the investigator in 26 cases (5%). The most common side Also, the effect of the 0.4 mg. dose in the 0.8 mg. group was effects in at least 5 patients (1% or greater) that led to the comparable to that in the 0.4 mg. group (decrease 3.8 and discontinuation of treatment were urinary retention in 17 about 4.2 points, respectively, fig. 2, B). Increasing the dose (3.3%, none considered drug related), prostatic disorder in 7 to 0.8 mg. had no substantial additional effect on the total (1.4%, 1 considered drug related), dizziness in 5 (1%, all symptom score. There was an increase of 0.1 points during considered drug related) and impotence in 5 (1%, 3 consid- ered drug related). A total of 117 patients (23%) had serious Treatment responders and quality of life. Figure 3 shows side effects during tamsulosin treatment for up to 4 years. In the incidence of patients considered to have a total Boyarsky addition, 2 patients died, including 1 from cardiac arrest and symptom score response (25% or greater improvement) at 1 in a motor vehicle accident. The deaths were not related to each time point. The number of total symptom score respon- tamsulosin according to the investigator. Serious side effects dents increased over the initial 14 weeks of tamsulosin treat- that were considered drug related, such as urinary inconti- FIG. 1. Long-term tamsulosin treatment. A, mean maximum urinary flow with time. At baseline and during treatment SD was 32 and 3.6 to 4.7 ml. per second, respectively. B, mean Boyarsky symptom score with time. At baseline and during treatment SD was 3 and from 2.6to 3.5 points during treatment, respectively. Versus baseline at all time points p Ͻ0.001.
FIG. 2. A, mean maximum urinary flow with time. B, mean total Boyarsky symptom score with time. At baseline and 12 weeks 89 patients, 24 weeks 74, 36 weeks 59, 48 weeks 54, 60 weeks 47, 72 and 84 weeks 44, 96 to 120 weeks 34 to 39 and 132 weeks 28.
LONG-TERM TAMSULOSIN USE FOR URINARY TRACT SYMPTOMS FIG. 3. Treatment responders during long-term tamsulosin treatment. A, 25% or greater decrease in total Boyarsky symptom score from baseline. B, 30% or greater increase in maximum urinary flow (Qmax) from baseline.
TABLE 4. Cumulative incidence of all reported and drug related standing diastolic blood pressure compared with baseline. In side effects in 515 patients treated with tamsulosin for up to 4 addition, no clinically relevant changes in laboratory param- Our analysis shows that the efficacy of 0.4 mg. tamsulosin once daily is sustained up to 4 years. Patients respond rap- idly to tamsulosin and the improvement in symptoms that is achieved within a few weeks is sustained during long-term treatment. The improved maximum urine flow and decreased symptom score are comparable to those in short-term During this long-term extension study only 18% of patients who did not respond optimally to 0.4 mg. tamsulosin and did not report any drug related side effects had a dose increase to 0.8 mg. However, this dose increase seems not to have had a substantial additional benefit based on improvements in symptom score and maximum urine flow. Previously others have also observed equal efficacy of 0.4 and 0.8 mg. tamsu-losin.4, 5, 10 The only statistically significant difference in the2 groups was a larger decrease in symptom score in the 0.8 nence, angina pectoris, penis disorder, cerebrovascular acci- mg. group in 1 study. However, this difference was already dent and dizziness, developed in only 5 patients (1%). The evident after 1 week of tamsulosin treatment when patients most common serious side effect in at least 5 patients (1% or in the 0.8 mg. group were still on the 0.4 mg. dose.5 This greater) were urinary retention in 17 (3.3%), prostatic disor- finding indicates that the different effect on total symptom der in 9 (1.7%), angina pectoris in 7 (1.4%) and prostatic score was more likely caused by differences in the response in carcinoma in 7 (1.4%). Of the 12 cases of urinary retention patient groups than by differences in the response to the 0.4 that were severe enough to require hospitalization (acute urinary retention), 5 (1%) developed within 1 and 7 (1.4%) Throughout the study period, tamsulosin was well toler- ated and the good safety profile was maintained up to 4 Table 5 shows standing and systolic blood pressure, and years. Side effects considered to be probably or possibly re- pulse rate at baseline and end point. Tamsulosin induced a lated to tamsulosin were reported in 26% of cases. Only 5% of small but statistically significant change in supine and patients discontinued treatment due to these side effects.
TABLE 5. Supine and standing systolic and diastolic blood pressure, and pulse rate in patients treated with tamsulosin for up to 4 years LONG-TERM TAMSULOSIN USE FOR URINARY TRACT SYMPTOMS The most commonly reported drug related side effects were urine flow and total Boyarsky symptom score were already dizziness in 5.8% of cases and abnormal ejaculation in 4.3%.
significant after 4 weeks, when the initial assessment was Other drug related side effects often associated with ␣1- made in the controlled studies, and they were sustained for adrenoceptor antagonists occurred at an incidence of less up to 4 years of followup in patients who remained in the than 3%. The incidence of drug related side effects in this study. The safety profile also remained favorable during this series was greater than in short-term 12-week placebo- controlled studies.8 Since in open label long-term studies no Ismar Healthcare NV assisted with manuscript editing.
placebo group is included, it is difficult to evaluate the inci-dence of side effects because the cumulative incidence ofcommon side effects tends to increase with time.
In European and American clinical trials abnormal ejacu- lation was the only side effect that was or was not drug 1. Denis, L., McConnell, J., Yoshida, O. et al: Recommendations of related that occurred more often with 0.4 mg. tamsulosin the International Scientific Committee: the evaluation and once daily than placebo (4.5% to 11% of cases).5, 8, 10 Abnor- treatment of lower urinary tract symptoms (LUTS) suggestive mal ejaculation, reported predominantly as retrograde ejac- of benign prostatic obstruction. In: Proceedings of the 4th ulation and decreased or absent ejaculate volume, is probably International Consultation on Benign Prostatic Hyperplasia related to the mode of action of ␣1-adrenoceptor antagonists, (BPH); 1997 Jul 2–5. Edited by L. Denis, K. Griffiths, S.
Khoury et al. Plymouth: Health Publication, p. 669, 1998 that is the relaxation of smooth muscle in the bladder neck, 2. Lepor, H., Kaplan, S. A., Klimberg, I. et al: Doxazosin for benign vas deferens and seminal vesicles. Direct comparative trials prostatic hyperplasia: long-term efficacy and safety in hyper- of tamsulosin and alfuzosin9, 11 or terazosin12, 13 have shown a tensive and normotensive patients. Multicenter Study Group.
comparable rate of abnormal ejaculation. Generally it is a J Urol, 157: 525, 1997
well tolerated side effect. In this long-term extension study 3. Lepor, H.: Long-term efficacy and safety of terazosin in patients only 1 patient (0.2%) discontinued treatment due to abnor- with benign prostatic hyperplasia. Terazosin Research Group.
Urology, 45: 406, 1995
Acute urinary retention is the major complication of lower 4. Lepor, H.: Long-term evaluation of tamsulosin in benign pros- urinary tract symptoms/BPH and in this study it was re- tatic hyperplasia: placebo-controlled, double-blind extension of
phase III trial. Tamsulosin Investigator Group. Urology, 51:
ported as a side effect. It may be considered an end point of lower urinary tract symptoms/BPH treatment that should be 5. Narayan, P. and Lepor, H.: Long-term, open-label, phase III prevented. The incidence of acute urinary retention during multicenter study of tamsulosin in benign prostatic hyperpla- watchful waiting or in placebo arms of clinical trials is low at sia. Urology, 57: 466, 2001
1% to 1.5% yearly.14–16 In this long-term study 17 patients 6. Schulman, C. C., Cortvriend, J., Jonas, U. et al: Tamsulosin: (3.3%) in 4 years were hospitalized due to acute urinary 3-year long-term efficacy and safety in patients with lower retention. This incidence is comparable to that documented urinary tract symptoms suggestive of benign prostatic obstruc- for finasteride in a 4-year study17 and it warrants further tion: analysis of a European, multinational, multicenter, open- label study. European Tamsulosin Study Group. Eur Urol, 36:
After 4 years of tamsulosin treatment 34% of patients were 7. Abrams, P., Schulman, C. C. and Vaage, S.: Tamsulosin, a se- still participating in the study. The discontinuation rate was lective alpha 1C-adrenoceptor antagonist: a randomized, con- comparable at most visits except at visit 6 (1 year). The much trolled trial in patients with benign prostatic obstruction higher withdrawal rate at this visit was attributable to the (symptomatic BPH). European Tamsulosin Study Group. Br J fact that patients were required to participate in the study Urol, 76: 325, 1995
for at least 1 year. Often patients withdraw from open label 8. Chapple, C. R., Wyndaele, J. J., Nordling, J. et al: Tamsulosin, studies because they no longer desire frequent visits and the first prostate-selective ␣ -adrenoceptor antagonists. A associated assessments, especially when the product be- meta-analysis of two randomized, placebo-controlled, multi- comes commercially available. This factor was clearly re- centre studies in patients with benign prostatic obstruction flected in the high discontinuation rate in all geographic (symptomatic BPH). European Tamsulosin Study Group. Eur areas in which tamsulosin became commercially available Urol, 29: 155, 1996
9. Buzelin, J.-M., Fonteyne, E., Kontturi, M. et al: Comparison of during the study period. Therefore, the number of patients tamsulosin with alfuzosin in the treatment of patients with who remain on long-term therapy in practice may be higher lower urinary tract symptoms suggestive of bladder outlet obstruction (symptomatic benign prostatic hyperplasia). Euro- The most important side effects of ␣1-adrenoceptor antag- pean Tamsulosin Study Group. Br J Urol, 80: 597, 1997
onists are dizziness, asthenia and postural hypotension. In 10. Narayan, P. and Tewari, A.: A second phase III multicenter the group of ␣1-adrenoceptor antagonists 0.4 mg. tamsulosin placebo-controlled study of 2 dosages of modified release tam- and alfuzosin have the lowest degree of these side effects.18 sulosin in patients with symptoms of benign prostatic hyper- However, alfuzosin has a more pronounced effect on blood plasia. United States 93-01 Study Group. J Urol, 160: 1701,
pressure than tamsulosin, especially in elderly patients.19 The current study also indicates no clinically significant 11. Ho¨fner, K., Claes, H., De Reijke, T. M. et al: Tamsulosin 0.4 mg daily: effect on sexual function in patients with lower urinary change in blood pressure and a lower incidence of side effects tract symptoms suggestive of benign prostatic obstruction. Eur often associated with ␣1-adrenoceptor antagonists, such as Urol, 36: 335, 1999
dizziness and asthenia, for tamsulosin than in other open 12. Lee, E. and Lee, C.: Clinical comparison of selective and non- label studies of terazosin and doxazosin.2, 3 This finding con- selective ␣1A-adrenoceptor antagonists in benign prostatic hy- firms direct comparative data showing fewer vasodilatory perplasia: studies on tamsulosin in a fixed dose and terazosin drug related side effects for tamsulosin than equieffective in increasing doses. Br J Urol, 80: 606, 1997
doses of terazosin.12, 13, 20 Overall tamsulosin has efficacy 13. Na, Y. J., Guo, Y. L., Gu, F.-L.: Clinical comparison of selective comparable comparable to that of other ␣1-adrenoceptor an- and non-selective alpha1A-adrenoceptor antagonists for blad- tagonists but a much better safety profile.
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14. Jacobsen, S. J., Jacobsen, D. J., Girman, C. J. et al: Natural history of prostatism: risk factors for acute urinary retention.
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15. Wasson, J. H., Reda, D. J., Bruskewitz, R. C. et al: A comparison Improvement in the primary efficacy parameters, maximum of transurethral surgery with watchful waiting for moderate LONG-TERM TAMSULOSIN USE FOR URINARY TRACT SYMPTOMS symptoms of benign prostatic hyperplasia. Veterans Affairs 18. Djavan, B., Marberger, M.: A meta-analysis on the efficacy and Cooperative Study Group on Transurethral Resection of the tolerability of alpha1-adrenoceptor antagonists in patients Prostate. N Engl J Med, 332: 75, 1995
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of patients with benign prostatic hyperplasia as diagnosed by 19. de Mey, C., Terpstra, I.: Orthostatic effects of alfuzosin twice North American urologists. J Urol, 157: 10, 1997
daily vs. tamsulosin once daily in the morning. J Urol, suppl., 17. McConnell, J. D., Bruskewitz, R., Walsh, P. et al: The effect of 163: 220, abstract 978, 2000
finasteride on the risk of acute urinary retention and the need 20. De Mey, C., Michel, M. C., McEwen, J. et al: A double-blind for surgical treatment among men with benign prostatic hy- comparison of terazosin and tamsulosin on their differential perplasia. Finasteride Long-Term Efficacy and Safety Study effects on ambulatory blood pressure and nocturnal orthostatic Group. N Engl J Med, 338: 557, 1998
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