Medical Therapy for Benign Prostatic Hyperplasia - Present and Future Impact

February 1, 2007
Muta M. Issa, MD, MBA

,
Timothy S. Regan, BPharm, RPh, CPh

Supplements and Featured Publications, Evaluating Real-world Clinical and Economic Outcomes in the Management of Enlarged Prostate - A New , Volume 13, Issue 1 Suppl

The purpose of this manuscript is to provideclinicians, health plan decision makers, and policymakers with highlights of key findings pertainingto our current understanding of the condition ofenlarged prostate (EP) from a managed careperspective. This includes a brief discussionregarding the prevalence and economic burdenof EP, followed by a review of clinical characteristicsand pathophysiology, with the final sectionon treatment approaches with a focus onpharmacologic options. This supplement is notintended to be a comprehensive review of EP,because many review articles on this subject areavailable elsewhere. This manuscript does,however, serve to introduce 3 additionalmanuscripts contained within this supplement.

The first article provides the readers with areal-world comparison of dutasteride and finasteriderelative to acute urinary retention andsurgery attenuation rates. The second articleinvestigates differences in discontinuation ratesof alpha blockers when used in combinationwith dutasteride or finasteride. The last articleaddresses the cost implications associatedwith dutasteride and finasteride therapy. All 3articles represent data from a naturalistic,managed care population.

This supplement is intended to assist managedcare formulary decision makers in evaluatingkey clinical and economic data which could helpto differentiate dutasteride and finasteride.Although the information presented does notprove superiority of either product, it will answersome important questions and raise someimportant issues beyond ingredient cost.

(Am J Manag Care. 2007;13:S4-S9)

With the advent of the Medicare Modernization Actand the introduction of a drug benefit for eligiblebeneficiaries, health plans and policy makers arenow realizing the need for potential shifts in diseasemanagement priorities. This is especially true for certain subsets of thepopulation, such as elderly men. United States Census informationsuggests that from the year 2000 to 2020, the number of men older thanthe age of 64 will grow to nearly 9.3 million.1 In a recent retrospectivestudy of men 50 years of age and older in a managed care population,coronary artery disease, hyperlipidemia, hypertension, type 2 diabetes,osteoarthritis, and enlarged prostate (EP) were the most prevalentdiagnoses (Table 1).2 Perhaps the most surprising finding from thisstudy was the inclusion of EP among the 5 most prevalent diseases.Although previously not on the "radar screen" for most health plans,EP may become one of the new priorities for disease management inthis rapidly growing population of men currently or soon to be eligiblefor Medicare.

This supplement is not intended as a comprehensive review of EP,because this topic has been reviewed elsewhere.3-5 Instead, our purposeis to provide clinicians, health plan decision makers, and policy makerswith some key findings pertaining to our current understanding ofthis important condition from a managed care perspective. Thisincludes a brief discussion of the prevalence and economic burden ofEP, the clinical characteristics and pathophysiology, and treatmentapproaches with a focus on pharmacologic options.

DISEASE PREVALENCE ANDECONOMIC BURDEN

Enlarged prostate or benign prostatic hyperplasia (BPH) is a chronicprogressive urologic condition6 which affects a significant number ofthe aging male population.7-10 The prevalence of moderate-to-severelower urinary tract symptoms (LUTS) is 26% in men aged 40 to 49years and 46% in men aged 70 and older.7 An estimated 1 in 4 menwill seek medical care for management of symptomatic BPH by age80.11-13 Approximately 90% of men have histologic evidence of the diseaseby age 85.11

The reported economic burden estimates of EPvary depending on the data sets studied. The incrementaldirect annual cost per patient associatedwith a diagnosis of EP has been estimated between$1536 and $2577 in 1999.7,14 Data from the early1990s estimate the cost of treatment to be $4 billionannually.15 In an analysis of privately insured menbetween the ages of 45 and 64 years, the estimatedannual healthcare expenditure to treat BPH inthis population was $3.4 billion in 1999.14 Finally,the Urologic Diseases in America BPH Project indicatedthat in the year 2000, the disease carried aneconomic burden of $1.1 billion in direct annualhealthcare expense in the United States, exclusiveof outpatient pharmacotherapy costs.7

Since the late 1980s, pharmacologic therapy utilizationhas increased while more invasive surgicalinterventions have declined.7,16,17 It is anticipatedthat treatment cost will continue to be adjusted asthis trend continues. At the same time, populationestimates provide a trajectory of increasing costs asthe number of treatment-eligible men expands.

The economic burden should not overshadowthe tremendous impact of EP on patients' quality oflife. As severity of voiding symptoms increases, menexperience a significant compromise in their overallwell-being. For men with severe symptoms, thegreatest impact appears to be on role limitationsdue to physical problems, energy/fatigue, role limitationsdue to emotional problems, and generalperception of health.18 These data support the importanceof quality of life in the assessment of medicaloutcomes and treatment decisions with thiscondition.

CLINICAL CHARACTERISTICSAND PATHOPHYSIOLOGY

The clinical impact of an EP is characterized byLUTS—including urinary frequency, urgency, nocturia,weak stream, hesitancy, and straining—withan increasing risk of clinical events, such as acuteurinary retention (AUR) or surgery. Recent evidencesuggests that the likelihood of AUR and/orsurgery occurring within 1 year of initiating treatmentis approximately 19%.19

The pathophysiology of EP includes both staticand dynamic components. Abnormal and excessivenonmalignant growth of prostate tissue is a hallmarkof the disease. Over time, the tissue growthstarts impinging on the prostatic urethra and thebladder neck, leading to bladder outlet obstruction.This is the static component of prostatichyperplasia. Continued exposure of the prostate todihydrotestosterone (DHT) plays a central pathophysiologicrole in this age-associated prostategrowth and eventual hyperplasia. There is also anincrease in the amount and tone of the smoothmuscle within the prostate. Stimulation of alpha1-adrenergic receptors on the bladder neck, prostaticcapsule, and stromal tissue results in constriction ofthe urethral lumen. This is the dynamic componentof prostatic hyperplasia. Although other factors areinvolved in the pathophysiology of LUTS,20 these2 components provide a rationale for the 2 mainpharmacologic approaches to BPH: alpha1-adrenergicantagonists (alpha1 blockers) and 5-alpha reductaseinhibitors (5ARIs).

TREATMENT APPROACHES WITHA FOCUS ON PHARMACOLOGICMANAGEMENT

Since the advent of effective medical therapy,the rate of surgical intervention for patients withsymptomatic EP has progressively and substantiallydecreased. Once among the most commonly practicedsurgical procedures, transurethral resection ofthe prostate is now performed much less frequentlybecause of the availability of pharmacologictreatment options as well as minimally invasiveprocedures.7

Evidence-based practice guidelines for the therapeuticapproach to EP were published by theAmerican Urological Association (AUA) in 200312and updated in 2006.13 The classic treatment goalsfor EP are to reduce LUTS, arrest disease progression,and prevent complications.21

The AUA Symptom Index (AUASI) is used tocategorize disease severity and aid in assessing treatmentresponse.12,13 The AUASI is a 7-item self-assessmentquestionnaire (identical to the 7symptom items of the International ProstateSymptom Score [IPSS]) that focuses on LUTS. The7 questions are answered on a scale of 0 to 5 basedon the presence and frequency of the symptomsexperienced by the patient during the precedingmonth. Total scores can range from 0 to 35.AUASI/IPSS scores <7 indicate mild disease, 8 to19 moderate disease, and >20 severe disease.

Treatment approaches to EP include watchfulwaiting, pharmacologic intervention, minimallyinvasive therapies, and surgical options (Table 2).According to the AUA guidelines on BPH, a strategyof watchful waiting is appropriate in patientswith mild symptoms of BPH (AUASI <7) and inpatients with moderate or severe symptoms(AUASI >7) who are not bothered by their symptoms(ie, the symptoms do not interfere with dailyactivities).12,13 Watchful waiting is also an optionfor patients with bothersome symptoms who havenot yet developed complications (eg, AUR, recurrentinfection, renal insufficiency); however, therisks and benefits of the various treatment options(including the risk of disease progression and complicationswith watchful waiting) should be discussedwith these patients. Patients on watchfulwaiting are usually monitored annually.12,13

The AUA guidelines recommend that pharmacotherapeuticintervention should be considered inpatients with bothersome symptoms and a score of>8 on the AUASI.12,13 Pharmacologic therapies forsymptomatic BPH include alpha1 blockers and5ARIs; however, 5ARIs are appropriate only whenthere is evidence of prostate enlargement. Patientswith prostate enlargement and nonbothersomesymptoms also may be offered 5ARI therapy to preventdisease progression.12,13 Prostate enlargementhas been defined as a prostate volume >30 cc.22

Alpha1 blockers target smooth muscle receptorsin the fibromuscular stroma of the prostate andbladder neck,20 relaxing the smooth muscle fibersat the bladder outlet and making it easier for thepatient to urinate. These agents include 2 therapiesnow available generically (doxazosin and terazosin)and 2 branded drugs, Flomax&#174; (tamsulosin) andUroxatral&#174; (alfuzosin). Prazosin is not approved bythe US Food and Drug Administration for treatmentof BPH.

The 1997 AUA Gallup survey indicated thatalpha blockers are the most frequently used pharmacologicintervention for BPH. According to the survey,alpha blockers are prescribed for 88% and 69%of moderately symptomatic patients with prostatevolumes <40 cc and >40 cc, respectively.23 However,although alpha blockers work effectively torapidly relieve bladder symptoms, they are consideredpurely symptom-modifying therapy rather thandisease-modifying therapy. They do not reduceprostate size and, therefore, do not prevent diseaseprogression or reduce the long-term risks of AURand the need for invasive treatment.24

Alpha blockers are generally well tolerated.Class side effects include orthostatic hypotension,dizziness, tiredness, ejaculation problems, and nasalcongestion.12,13 There are, however, differences inthe adverse-effect profiles among the various alphablockers. Alfuzosin (especially the XL formulation)and tamsulosin (especially the 0.4-mg/day dose) arebetter tolerated than doxazosin and terazosin.25Tamsulosin is the least likely to cause vasodilatoryside effects, and the most likely to cause abnormalejaculation.25

There are 2 marketed 5ARIs, finasteride(Proscar&#174;, now also available generically) anddutasteride (Avodart&#174;). Their main pharmacologicaction is inhibition of 5-alpha reductase, theintraprostatic enzyme that converts testosteroneand androstenedione to DHT.26,27 This decreasesDHT concentrations within the prostate tissue,resulting in a reduction in prostate size. Comparedwith placebo, the 5ARIs produce significant reductionin prostate volume and improvement in symptomscores as well as significant decreases in AURand surgical intervention rates.28-30

Combination treatment with an alpha blockerand a 5ARI is emerging as the medical treatment ofchoice for patients with LUTS who have EP (>40 g)glands as suggested in the 2003 AUA treatmentguidelines.12,13 The alpha blocker component ofthe combination therapy provides early symptomcontrol, while the 5ARI component addresses diseaseprogression leading to long-term symptomcontrol.

The Medical Therapy of Prostatic Symptoms(MTOPS) trial, which enrolled patients between1993 and 1998, provides the most definitive datasupporting dual therapy.24 The study objective wasto evaluate whether an alpha blocker (doxazosin) ora 5ARI (finasteride), alone or in combination,would impact disease progression. Although allactive therapies provided significant symptom scoreimprovements and reduced the risk of overall clinicalprogression (defined as an increase of >4 pointson the AUASI, AUR, urinary incontinence, renalinsufficiency, or recurrent urinary tract infection),the risk reduction associated with dual therapy(66%) was significantly greater compared witheither agent alone (39% doxazosin, 34% finasteride).The long-term risks of AUR and invasivetherapy were significantly reduced by finasteridealone or in combination with doxazosin, but not bydoxazosin alone.

As mentioned previously, symptom controloccurs at 1 to 2 weeks with alpha blocker therapycompared with 3 to 6 months with 5ARIs. Thisunderstanding led several authors to investigate theimpact on symptom control of alpha blocker withdrawalafter initial combination treatment. In astudy conducted by Baldwin et al,31 272 men withprostate glands >40 g and with AUA scores >20were treated with a 5ARI (finasteride) and an alphablocker (doxazosin) in combination. Doxazosinwas discontinued at 3, 6, 9, or 12 months, whilecontinuing finasteride, and patients were re-evaluated1 month after alpha blocker discontinuation.Symptom control was most likely to be maintainedin patients who discontinued doxazosin atmonth 9 or 12; the authors concluded that alphablocker therapy could be successfully discontinuedat 9 months or later in patients initially treated withdoxazosin and finasteride.

A second study was conducted utilizing dutasteridein combination with the alpha blocker tamsulosin.32 This multinational, multicenter trialincluded 327 men with moderate-to-severe symptoms(IPSS >12) and prostate volumes >30 cc.Patients underwent 24 weeks of combined therapy,followed by a 12-week double-blind phase in whichthey were randomly assigned to continued dualtherapy or dutasteride monotherapy plus an alphablocker placebo. The primary end point was thepercentage of patients experiencing improvementor no change in symptoms between weeks 24 and30. Overall, 77% of participants who had alphablocker therapy withdrawn reported feeling thesame or better at week 30 than they did at week 24compared with 91% of those who continued dualtherapy. In the alpha blocker discontinuationgroup, 84% of those with IPSS <20 at baseline hadno deterioration in symptom control comparedwith 57.5% of those with IPSS >20 at baseline.The authors concluded that in a majority of patientstreated with combination therapy (dutasterideand tamsulosin), the alpha blocker can besuccessfully discontinued after 6 months of combinationtreatment, but that patients with severesymptoms may benefit from longer-term combinationtreatment.

Differences between these 2 studies in the timingof successful alpha blocker discontinuation maybe explained by the characteristics of dutasterideversus finasteride. Both 5ARIs work by inhibiting5-alpha reductase; however, dutasteride inhibitsboth the type-1 and type-2 isozymes of 5-alphareductase, whereas finasteride inhibits only type 2.Consistent with these distinct mechanisms, suppressionof serum DHT has been shown to be significantlygreater with dutasteride than withfinasteride.33 Furthermore, a recent nonrandomizedcomparative study demonstrated that a significantlygreater percentage of dutasteride-treated patientsexperienced symptom improvement at 3 monthscompared with finasteride-treated patients.34

These data may indicate that earlier symptomcontrol allows for earlier alpha blocker withdrawalin patients receiving combination therapy withdutasteride versus finasteride. Moreover, based onserum DHT results, it has been hypothesized thatmore prostate volume reduction may occur withdutasteride, and that this could translate to lowerAUR and surgery rates.

Beyond traditional treatment approaches withalpha blockers and/or 5ARIs, new concepts in medicaltherapy are emerging to include use of an alphablocker together with an antimuscarinic agent tohelp men suffering from irritative or storage symptoms.35 In addition, the use of phosphodiesterasetype 5 inhibitors are being explored in the medicaltherapy of BPH.36

This supplement is intended to assist managedcare formulary decision makers in evaluating keyclinical and economic data which could differentiatedutasteride and finasteride. The following 3analyses used data from a naturalistic, managed careenvironment to answer some important practicalquestions and raise some important issues beyonddrug cost.

The first article in the series is a real-world comparisonof dutasteride and finasteride with respectto AUR and surgery attenuation rates. The secondarticle investigates differences in time to discontinuationof alpha blockers when these agents are initiallyused in combination with dutasteride orfinasteride. The final article in the series evaluateseconomic differences in medical cost betweenpatients initiating 5ARI therapy.

Efforts focused on optimizing the use of our currentknowledge in the management of EP will likelyresult in improved outcomes and potentialreduction in healthcare resource utilization. In theyears ahead, the expected growth of the older malepopulation will continue to place a spotlight on thismen's health issue for managed care organizationsand healthcare providers, especially consideringnew Medicare Part D drug benefit changes.

Address correspondence to: Muta M. Issa, MD, MBA, Associate Professor of Urology,Emory University School of Medicine, 1440 Clifton Road NE, Atlanta, GA 30322. E-mail:issa@emory.edu.

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34. Hagerty JA, Ginsberg PC, Harkaway RC. A prospective,comparative study of the onset of symptomaticbenefit of dutasteride versus finasteride in men withbenign prostatic hyperplasia in clinical practice.Presented at: the 2004 Annual Meeting of the AmericanUrological Association; May 8-13, 2004; San Francisco,Calif. Poster 1353.

35. Macdiarmid S, Chen A,Tu N, Aquilina J, Peters K.Effects of tamsulosin and extended-release oxybutyninon lower urinary tract symptoms in men. Abstract presentedat: the 2006 Annual Meeting of the AmericanUrological Association; May 20-25, 2006; Atlanta, Ga.Abstract 1638.

36. Roehrborn CG, McVary K, Kaminetsky J, et al.The efficacyand safety of tadalafil administered once a day forlower urinary tract symptoms (LUTS) in men with benignprostatic hyperplasia (BPH). Abstract presented at: the2006 Annual Meeting of the American Urological Association;May 20-25, 2006; Atlanta, Ga. Abstract 1636.