Comparative Analysis of Alpha-blocker Utilization in Combination With 5-Alpha Reductase Inhibitors for Enlarged Prostate in a Managed Care Setting Among Medicare-aged Men

Published Online: May 01, 2008
Muta M. Issa, MD, MBA; Pei-Jung Lin, PhD; Michael T. Eaddy, PharmD, PhD; Manan B. Shah, PharmD, PhD; and E. Anne Davis, PharmD, MS

Objective: To evaluate the likelihood of alphaadrenergic antagonist (alpha-blocker) discontinuation in combination with dutasteride or finasteride among patients aged =65 years with enlarged prostate.

Methods: This retrospective analysis used 2003- 2006 data representing more than 30 million managed care members. Medical/pharmacy claims were used to select patients, matched 1:1 using propensity scoring. The proportion remaining on alpha-blocker therapy more than 12 months and time to discontinuation were compared between groups, controlling for covariates using survival analysis.

Results: The matched sample included 1674 patients. Alpha-blocker therapy discontinuation was observed at 90 days (86.9% dutasteride patients and 91.8% finasteride patients remained on alpha-blocker therapy). After 12 months, more dutasteride patients discontinued (38.1% remained) alpha-blocker therapy than finasteride patients (56.3% remained).

Conclusions: Patients discontinued alpha-blocker therapy as early as 3 months. Those taking dutasteride were 64% more likely to discontinue alpha-blocker therapy than patients taking finasteride. Dutasteride’s impact on discontinuation may have important implications and should be examined further.

(Am J Manag Care. 2008;14:S160-S166)

Enlarged prostate (EP), or benign prostatic hyperplasia (BPH), is the fourth most commonly diagnosed medical condition1 in older men and most often affects men aged ≥50 years. It has been estimated that 1 of 4 men will seek medical care for EP by 80 years of age.2 The disease burden is large and accounts for 4.5 million outpatient visits and $1.1 billion in total direct medical costs in the United States.3 Because the disease incidence increases with advancing age, the population at risk is expected to expand with the general population maturing. The US Census Bureau projects that the population of men aged ≥45 years will grow by 45% to 64.7 million by 2020.4 As more patients enroll in Medicare health plans and obtain a prescription drug benefit, the need to evaluate the comparative effectiveness for EP treatment options in the real world becomes paramount.

There are 2 pharmacologic approaches to the management of EP: alpha-adrenergic antagonists (alpha-blockers) and 5-alpha reductase inhibitors (5ARIs). Alpha-blockers are used to provide symptomatic relief; however, they do not alter the disease progression of prostate enlargement.5,6 The American Urological Association recommends 5ARIs to reduce prostatic growth in patients with demonstrable EP. Reduction in prostate size relieves urinary symptoms and decreases the progression rate for acute urinary retention (AUR) and prostaterelated surgeries.5,7

The clinical benefits of 5ARIs can take several months to be apparent; therefore, many clinicians initially use the combination of alpha-blockers and 5ARIs. Combination therapy has been shown to reduce disease progression compared with either drug class alone.8 It has also been shown that alpha-blocker therapy can be stopped after 6 months of treatment without compromising the level of symptom control.9

Although both dutasteride and finasteride are 5ARIs, their pharmacologic and clinical profiles are distinct. Dutasteride inhibits both type 1 and type 2 alpha-reductase isoenzymes and can suppress more than 90% of dihydrotestosterone (DHT) production. In comparison, finasteride blocks only the type 2 isoenzyme, providing partial inhibition, and has a much shorter half-life (5-6 hours for finasteride vs 5 weeks for dutasteride).7,10-12 Recent investigations have indicated that patients treated with dutasteride produce faster symptom relief, lower complication risks for AURs, and reduced incidences of prostate-related surgeries compared with finasteride.1,13,14 Symptom improvements occur in a greater proportion of dutasteridetreated patients within 3 months of initiation compared with finasteride.14 This is further supported by Naslund et al, who found that within 1 year of combination therapy a greater proportion of patients aged ≥50 years receiving dutasteride discontinued alpha-blockers 20% earlier compared with finasteride.15 Faster symptomatic control could provide earlier alphablocker withdrawal while reducing overall treatment costs and the possible additional exposure to alphablocker side effects.

Because of the need to further explore the outcome differences between 5ARI agents among the expanding elderly population, this study examined alpha-blocker utilization in an older patient population (≥65 years) in combination with dutasteride or finasteride treatment.

Sample Selection
Deidentified patient data were collected from the Ingenix Lab/Rx proprietary research database for the 3-year period between July 1, 2003, and June 30, 2006. The Ingenix Lab/Rx database contains medical and pharmacy claims representing more than 30 million covered managed care lives and consists of up to 10 years of historical data spanning from the Midwest and Southern regions of the United States. Data analysis included both inpatient and outpatient diagnoses as determined by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes16 and procedures as specified in the Current Procedural Terminology 4 formats, as well as prescription records. Dates of service and both paid and charged amounts were available for all services rendered.

Male patients aged ≥65 years diagnosed with EP and treated with either dutasteride or finasteride and an alpha-blocker (eg, doxazosin, prazosin, terazosin, tamsulosin, or alfuzosin) were eligible for inclusion. The alpha-blocker prescription was required to have been issued on or before the 5ARI prescription date and to have continued for at least 45 days after the initial 5ARI prescription date. Patients were excluded if they were diagnosed with bladder or prostate cancer, were receiving nontherapeutic dosages of dutasteride or finasteride (eg, treated for male pattern baldness), or had used both 5ARIs during the 12- month evaluation period. Table 1 lists all relevant inclusion and exclusion ICD-9-CM codes.

Assessment of Alpha-blocker Discontinuation The likelihood of alpha-blocker discontinuation was evaluated over a 12-month period. Time to alphablocker discontinuation was measured from the start of combination therapy to the last prescription date for alpha-blocker treatment. If the time to discontinuation was more than 12 months, the patient was classified as having received therapy for 365 days.

Comorbidity Assessment
Comorbidities within the study population were evaluated based on the Charlson Comorbidity Index (CCI) with the Dartmouth-Manitoba and Deyo modification.17,18 This index includes 19 medical conditions, each assigned with a weight scale ranging from 1 to 6. The maximum possible score ranges from 0 to 33. Higher scores correlate with greater burdens of comorbidities.17

Staging of EP
The Thomson Medstat Disease Staging coding methods were used to determine EP-related complications before 5ARI therapy.19 The Thomson Medstat method is a proprietary coding criteria based on electronic screening and identification of a comprehensive map of ICD-9-CM diagnosis codes. This method is 1 of 4 systems selected for dissemination with the Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample and has been widely utilized as a classification system for diagnostic categories.

There are 7 ascending ICD-9-CM code criteria used for staging the severity of prostate enlargement (Table 2). Patients initiated on 5ARI treatment in this study were categorized into 1 of the 7 disease severity stages based on these codes. Patients categorized as ≥stage 1.2 were deemed to have complicated EP. Patients with hematuria (ICD-9-CM code 599.7) and/or bladder stones (ICD-9-CM codes 592.0, 592.1, 592.9, and 594.1) were also identified to capture additional severity risks.19

Analysis of Outcomes
Propensity score matching was utilized to normalize the probability of receiving treatment with either of the 5ARIs, given the following covariates: age, CCI, prior alpha-blocker use, history of AUR, use of urologist care, bladder stones, hematuria, and the presence of prostate-related complications. This was performed using a 1:1 caliper match (0.001) so that every dutasteride patient was propensity score–matched (±0.001) to one finasteride patient. Univariate analyses of frequencies and means were performed to characterize the demographics of the study population. Chi-square and t-tests were used to compare differences among dichotomous and continuous variables, respectively.

The likelihood and timing of alpha-blocker discontinuation were assessed via survival analysis techniques. Time to discontinuation was modeled as a function of age, CCI, use of uroselective alpha-blockers, number of prior alpha-blocker prescriptions, history of AUR, number of prostate-related office visits, bladder stones, hematuria, and Thomson Medstat stage using a Cox proportional hazards model. Cox proportional hazards models measure the likelihood of an event occurring over a defined time period in the presence of condition A compared with condition B. This likelihood is expressed as a hazard ratio (HR). HRs >1 are interpreted to mean that an event is more likely to occur under condition A versus B; ratios <1 indicate that an event is less likely to occur under condition A versus B; ratios equal to 1 indicate that an event is equally likely to occur under either condition. The HR also represents the instantaneous potential per unit of time for an event to occur, given that the event has not already occurred. Therefore, the HR represents the average likelihood over the entire time assessed, not just the end of the assessment period. All statistical analyses were conducted using SAS version 9.1.3, with an a priori significance level of alpha = 0.05.

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