title: Influence of baseline variables on changes in International Prostate Symptom Score after combined therapy with dutasteride plus tamsulosin or either monotherapy in patients with benign prostatic hyperplasia and lower urinary tract symptoms: 4-year results of the CombAT study.
abstract: OBJECTIVE
  To examine, using post hoc analysis, the influence of baseline variables on changes in international prostate symptom score (IPSS), maximum urinary flow rate (Qmax ) and IPSS quality of life (QoL) in patients with moderate-to-severe lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) treated with either the α-blocker tamsulosin or the dual 5-alpha reductase inhibitor dutasteride, alone or in combination, as part of the 4-year Combination of Avodart and Tamsulosin (CombAT) study.
  
  
  METHODS
  CombAT was a 4-year, multicentre, randomized, double-blind, parallel-group study in 4844 men ≥50 years of age with a clinical diagnosis of BPH by medical history and physical examination, an IPSS ≥12 points, prostate volume (PV) ≥30 mL, total serum PSA level ≥1.5 ng/mL, and Qmax >5 mL/s and ≤15 mL/s with a minimum voided volume ≥125 mL. Eligible subjects were randomized to receive oral daily tamsulosin, 0.4 mg; dutasteride, 0.5 mg; or a combination of both. Baseline variable subgroups analysed were as follows: PV (30 to <40; 40 to <60; 60 to <80; ≥80 mL), PSA level (1.5 to <2.5; 2.5 to <4; ≥4 ng/mL), age (median: <66, ≥66 years), IPSS (median: <16, ≥16; IPSS thresholds, <20, ≥20), IPSS QoL score (question 8, Q8) (median: <4, ≥4), Qmax (median: <10.4, ≥10.4 mL/s), BPH impact index (BII) (median: <5, ≥5) and body mass index (BMI, median: <26.8, ≥26.8 kg/m(2) ). Within each baseline variable subgroup, changes in IPSS, Qmax and IPSS QoL Q8 from baseline were evaluated using a generalized linear model with effects for baseline IPSS, Qmax or IPSS QoL Q8 and treatment group at each post-baseline assessment up to and including the month 48 visit using a last observation carried forward approach. The treatment comparisons of combination therapy vs dutasteride and combination therapy vs tamsulosin were performed from the general linear model with statistical significance defined as P ≤ 0.01.
  
  
  RESULTS
  Combination therapy resulted in a significantly greater improvement from baseline IPSS at 48 months vs tamsulosin monotherapy across all baseline subgroups. The benefit of combination therapy over dutasteride was confined to groups with lower baseline PV (<60 mL) and PSA (<4 ng/mL). In groups with baseline PV ≥60 mL and PSA ≥4 ng/mL, dutasteride and combination therapy show similar improvements in symptoms. Combination therapy resulted in significantly improved Qmax compared with tamsulosin but not dutasteride monotherapy. Qmax improvement appeared to increase with PV and PSA level in combination therapy subjects. The proportion of subjects with an IPSS QoL ≤2 (at least mostly satisfied) at 48 months was significantly higher with combination therapy than with dutasteride for subgroups with PV 40-60 mL and PSA level <4 ng/mL and than with tamsulosin for all PSA subgroups and PV subgroups ≥40 mL.
  
  
  CONCLUSIONS
  CombAT data support the use of long-term combination therapy with dutasteride and tamsulosin in patients considered at risk for progression of BPH, as determined by high PV (≥30 mL) and high PSA (≥1.5 ng/mL). Combination therapy, dutasteride monotherapy and tamsulosin monotherapy all improved Qmax , but to different extents (combination therapy > dutasteride >> tamsulosin), suggesting that dutasteride contributes most to the Qmax benefit in combination therapy. Combination therapy provided consistent improvement over tamsulosin in LUTS across all analysed baseline variables at 48 months. Compared with dutasteride, the superiority of combination therapy at 48 months was shown in patients with PV <60 mL or PSA <4 ng/mL.
authors.affiliation: Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Claus G
authors.initials: CG
authors.lastname: Roehrborn
authors.forename: Jack
authors.initials: J
authors.lastname: Barkin
authors.forename: Andrea
authors.initials: A
authors.lastname: Tubaro
authors.forename: Mark
authors.initials: M
authors.lastname: Emberton
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Wilson
authors.forename: Betsy J
authors.initials: BJ
authors.lastname: Brotherton
authors.forename: Ramiro
authors.initials: R
authors.lastname: Castro
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000008:administration & dosage*; D000208:Acute Disease; D000284:Administration, Oral; D000368:Aged; D001378:Azasteroids / Q000008:administration & dosage*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000379:methods; D000068538:Dutasteride; D006801:Humans; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000503:physiopathology; D053448:Prostatism / Q000188:drug therapy* / Q000503:physiopathology; D013449:Sulfonamides / Q000008:administration & dosage*; D000077409:Tamsulosin; D016896:Treatment Outcome; D016055:Urinary Retention / Q000188:drug therapy; D014554:Urination / Q000187:drug effects
chemical_list: D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D013449:Sulfonamides; D017430:Prostate-Specific Antigen; D000077409:Tamsulosin; D000068538:Dutasteride
keywords: IPSS; benign prostatic hyperplasia; combination therapy; dutasteride; prostate volume; tamsulosin