The Hidden Condition: Status, Challenges, and Opportunities in the Management of Enlarged Prostate for Managed Care

The American

Journal of Managed Care

This supplement to presents a comprehensive view of enlarged prostate, from its impact on older men to differential treatment outcomes as a result of various medical management strategies. The primary goal of this supplement is to provide managed care decision makers and clinicians with a better understanding of the significance of enlarged prostate. The results of retrospective claims analyses conducted in large managed care datasets were designed to provide a real-world perspective of treatment outcomes in enlarged prostate.

There are many challenges facing managed care, not least of which is the anticipated need for enlarged prostate-related care in a rapidly aging male population. This article provides the relevant background and setting for the remainder of this supplement, highlighting opportunities for managed care to impact the state of health in their male population and to make evidence-based treatment decisions. The elderly male population is of special interest in this supplement, in light of the recent changes to Medicare and potential effects to managed care. This article describes the current clinical, economic, and humanistic burden of benign prostatic hyperplasia (BPH), also known as enlarged prostate. The authors also provide a relevant review of enlarged prostate, including current practice patterns, management principles, and challenges that currently face providers and managed care payers.

Enlarged prostate is a prevalent condition in adult men which significantly increases with advancing age and affects not only long-term urinary health, but quality of life as well. Because men with enlarged prostate may not present to their healthcare provider until symptoms are severely bothersome or may never present to their healthcare provider, the actual economic and societal burden is difficult to assess.

Approaches to management include watchful waiting, medical management, and invasive or minimally invasive surgical therapy. Medical management is frequently the preferred first choice of many patients and providers, given the clinical evidence of safety and efficacy and relative ease of use. Of the pharmacotherapy available, 5-alpha reductase inhibitors offer not only symptom relief over long-term treatment, but the ability to directly impact disease progression in a noninvasive manner. Although alpha blockers provide rapid symptomatic relief of lower urinary tract symptoms (LUTS), they do not provide a reduction in the risk of developing acute urinary retention (AUR) or the need for surgery. The ability of medical therapy to impact the progression of enlarged prostate has many implications for managed care, including a potential reduction in the incidence of costly complications and enlarged prostate-related resource utilization.

Epidemiology

In the United States, the prevalence of enlarged prostate has been estimated at approximately 10%,¹ but increases with age from 3% to 26% in men aged 40 to 50 years to 24% to 90% in men =80 years of age.^1,2 This variance in prevalence rates presents a challenge in identifying men who should be receiving treatment for enlarged prostate. One reason for these differences is a historical underdiagnosis of enlarged prostate. For instance, population-based epidemiological studies tend to produce lower estimates of enlarged prostate^1,3 compared with studies utilizing histopathologically confirmed enlarged prostate.²

Reasons underpinning the low diagnosis of enlarged prostate include male health-seeking behaviors and attitudes, asymptomatic progression of enlarged prostate, and little public focus. Considering that much of the economic burden of illness for men with enlarged prostate comes from those who have been diagnosed, there is a hidden cost associated with enlarged prostate. As such, accurate estimates of the true economic burden are rare in the literature. Rather, predictions based on the cost of medical management estimate that the annual costs to the United States exceed $26 billion.⁴ Men with a diagnosis of enlarged prostate have been estimated to cost an incremental $2577 more than the annual medical costs of men without enlarged prostate.⁵ When considering the number of men at risk for enlarged prostate (ie, men >50 years of age), the incremental cost of treating enlarged prostate is significant to managed care health plans. As the population at risk for enlarged prostate continues to expand from 44.8 million men =45 years of age in 2000 to 64.7 million men in this age group by 2020,⁶ costs will continue to rise.

In addition to the economic burden, enlarged prostate can significantly impact patients' quality of life, affecting both physical and mental health. An Olmsted County, Minnesota, study, one of the largest urology-based epidemiological studies conducted in men, found that the severity of LUTS as rated by the American Urological Association (AUA) symptom score and bother index was strongly associated with physical functioning, general health perceptions, and role limitations.⁷ For example, there was a 44% decrease in health status scores for role limitations due to physical problems for men with severe LUTS versus men without LUTS.⁷ Similar trends were seen for health status as measured by social functioning, poor energy and fatigue, and emotional problems.⁷ Symptoms of enlarged prostate also negatively impact sexual functioning, an important component of health status and quality of life, as demonstrated by the Multinational Survey of the Aging Male.⁸ This survey found that, independent of age, erectile functioning and frequency of sexual activity decrease with increasing LUTS. Increased age causes an additional decline in function and frequency.⁹ Because enlarged prostate is not limited to men in retirement, its impact on workplace productivity can also be felt, with 10% of men younger than 65 years of age reporting some lost work or disability due to enlarged prostate.¹⁰ However, quantitative assessments of the true societal and economic burden of enlarged prostate to managed care are sparse because of the relative lack of attention given to this long-term condition.

Clinical Presentation

The primary challenge with enlarged prostate is its gradual, insidious progression. The extent of urethral obstruction and bladder contractility changes depend on the degree of prostate gland enlargement, which does not necessarily correlate with symptom severity.⁷ In fact, some men may have significantly enlarged prostates and either have no evident symptoms or no bothersome symptoms.¹¹ Typically, however, the first symptoms of enlarged prostate often manifest as nonspecific LUTS, such as a reduced urinary stream, urination hesitancy, or feelings of inadequate voiding.⁹ These symptoms are also common in other nonurological diseases or conditions, such as type 2 diabetes, Parkinson's disease, multiple sclerosis, and obesity. Medications for chronic conditions, such as diuretics, anticholinergic agents, and tricyclic antidepressants, can also produce LUTS. In addition, smoking and/or alcohol use can also contribute to LUTS. In clinical practice, enlarged prostate is typically diagnosed when patients present to their primary healthcare provider with complaints of LUTS and are found to have a palpably enlarged prostate gland on digital rectal examination or have an elevated prostate-specific antigen level. It is important, then, to differentiate LUTS secondary to enlarged prostate from LUTS from other conditions, medication adverse events, or prostate cancer.

BPH is a progressive condition, resulting in reductions in urinary flow and function. In the Olmsted County study, peak urinary flow rates declined an average of 2.1% per year and were correlated with advancing age.¹² Men with enlarged prostates (prostate volume >30 mL) had a significantly greater decline in peak urinary flow rate compared with men with smaller prostate volumes,¹² indicating the accelerated decline in urinary function in patients with enlarged prostate. A 7-year follow-up of the Olmsted County study cohort found similar trends with increasing prostate volume with age, for an average increase of 1.6% annually.¹³ Men with larger prostate volumes at baseline had significantly greater increases in prostate volume over time.¹³

Of concern to men with enlarged prostate are the risks of AUR and surgery. AUR is a significant complication of enlarged prostate and frequently necessitates catheterization and surgical intervention.¹⁴ The incidence of AUR has been reported to range from 0.5% to 2.5% per year,¹⁴ but because of the pathophysiology of enlarged prostate, men with greater prostate volume have an up to 3 times increased risk of AUR.¹⁵ Pain and discomfort, as well as the economic burden associated with AUR, surgical intervention for AUR, and surgery for enlarged prostate, are all significant. From a patient perspective, a survey conducted by Kawakami and Nickel indicated that 57% of men with enlarged prostate were concerned about the risk of developing AUR, and more than two thirds of men were concerned about the risk of surgery.¹⁶ As such, there is a need for a prospective, preventative approach towards the management of enlarged prostate similar to the management of many other long-term progressive diseases.

Approaches to Treatment

In general, there are 4 approaches to treating men with enlarged prostate–watchful waiting, medical management, minimally invasive therapy, and surgical therapy. One or multiple approaches can be effective, depending on the patient's wishes, financial status, and significance of symptom bother. Watchful waiting is an appropriate option for many men with enlarged prostate and consists of monitoring the patient for disease progression, deterioration, or onset of bothersome symptoms.^11,17

Medical management.

Therapy for enlarged prostate has historically been primarily surgical and symptom driven, initiated only when LUTS became bothersome to the patient. In recent years, there has been a shift in treatment for enlarged prostate from surgical therapy to medical management, partially reflective of the desire for early disease modification rather than symptomatic management alone. Although the number of invasive procedures, such as transurethral resection of the prostate (TURP) and open prostatectomy, has dropped significantly, outpatient visits for enlarged prostate increased by more than 4000 visits per 100 000 men from 1994 to 2000.⁵ In clinical practice, medical management is often considered first-line therapy for men with enlarged prostate, but pharmacotherapy should not always preclude initial therapy with invasive management,^11,18 because there are many patient-specific factors that must be considered when treating enlarged prostate.

With the introduction of alpha blockers and 5-alpha reductase inhibitors to clinical practice, medical management has seen a dramatic increase in use for men with LUTS of varying severity.¹⁹ Alpha blockers are primarily symptomatic treatment and have no impact on prostate volume or disease progression, ¹¹ whereas 5-alpha reductase inhibitors exert their therapeutic benefit by reducing prostate volume and thus slowing disease progression.^11,20 Algorithms indicating the appropriate role of the various treatment approaches to enlarged prostate have been developed by the AUA and the British Association of Urological Surgeons (Table).

Alpha blockers.

Alpha adrenergic blockers, the most commonly prescribed pharmacotherapy for enlarged prostate, are used for symptomatic relief of LUTS associated with enlarged prostate.⁵ These agents exert their therapeutic effect by preventing the alpha adrenergic-stimulated contraction of smooth muscle tissue in the prostate and bladder neck, which results in decreased resistance to urine flow and a decrease in LUTS in many men.^11,21

There are 4 alpha receptor blockers available to treat BPH: terazosin, doxazosin, tamsulosin, and alfuzosin. AUA guidelines state that all 4 alpha blockers have similar efficacy at improving urinary symptoms and urinary flow rate. The side effect profile of these 4 drugs varies somewhat. The older agents, terazosin and doxazosin, are not uroselective and require dose titration to decrease the risk of systemic vasodilation, hypotension, and syncope. The selective alpha blockers, tamsulosin and alfuzosin, do not require dose titration. The risks of dizziness, hypotension, and syncope are higher for terazosin and doxazosin than for alfuzosin and tamsulosin. There is an increased risk of ejaculatory dysfunction with tamsulosin.

Alpha blockers have excellent efficacy in improving LUTS caused by enlarged prostate. However, alpha blockers do not impact the long-term growth rate of the prostate and the resulting disease progression which occurs in many men with enlarged prostate. The risk of disease progression in men with enlarged prostate occurs because of prostate tissue growth stimulated by dihydrotestosterone (DHT). Alpha blockers do not alter this growth rate and therefore do not reduce the risk of AUR or the need for prostate surgery over the long term. The Medical Therapy of Prostatic Symptoms (MTOPS) trial, however, did demonstrate that alpha blockers can delay the onset of urinary retention for an average of 1 to 2 years in the clinical trial setting.²²

5-alpha reductase inhibitors.

Another class of medications available to treat prostate enlargement are 5-alpha reductase inhibitors (dutasteride and finasteride). These agents work by blocking the activity of the type I (dutasteride) and type II (dutasteride and finasteride) 5-alpha reductase enzymes. These enzymes are responsible for the conversion of testosterone to DHT, which is the primary androgen responsible for development and progression of enlarged prostate. With long-term administration, 5-alpha reductase inhibitors reduce prostate volume by 20% to 26%. This prostate volume decrease results in improvement in LUTS and urinary flow rate, reducing the risk of AUR and prostate surgery. The majority of the beneficial effects of 5-alpha reductase inhibitors take 6 to 12 months to become clinically apparent.

The efficacy of 5-alpha reductase inhibitors has been demonstrated in several double-blind placebo-controlled clinical trials with a 20% to 26% reduction in prostate volume, 3.3- to 4.4-point decrease in AUA symptom score, and improved urinary flow rate after 2 to 4 years of treatment.^23-25 Long-term clinical trials using 5-alpha reductase inhibitors have demonstrated that patients taking these medications have a significantly reduced risk of AUR and the need for prostate surgery over a 4-year period.^22,26 Because 5-alpha reductase inhibitors act by reducing prostate volume, beneficial clinical effects are most notable in men who have significant prostate enlargement. This subset of men is at a greater risk for enlarged prostate disease progression and clinically significant events, such as AUR and the need for prostate surgery.

The side effect profile of 5-alpha reductase inhibitors is different than that of alpha blockers. The most common adverse events with 5-alpha reductase inhibitors include erectile dysfunction, decreased ejaculate volume, and a decrease in libido.^11,25 There is also a 1% to 2% risk of nipple tenderness or gynecomastia. In general, if side effects occur and the medication is discontinued, the side effects are reversible, provided they were caused by the medication.

Because alpha blockers and 5-alpha reductase inhibitors have different mechanisms of action, there is a subset of men with LUTS from BPH in whom combination medical management using both agents can be beneficial. The advantage of alpha blockers in these men is the prompt relief of LUTS, whereas the advantage of 5-alpha reductase inhibitors is the shrinkage of the prostate and the long-term decreased risk of progression to retention and prostate surgery. Over the long run, there is also a decreased risk of symptom progression in men treated with 5-alpha reductase inhibitors. In some instances, men started on combination medical therapy can have the alpha blocker discontinued after approximately 1 year of treatment.²⁷

Phytotherapy.

Phytotherapy is widely used in both the United States and Europe as an over-the-counter option for men with LUTS. There are few randomized placebo-controlled trials on these agents, and the clinical results from those trials are not definitive. The advantage to phytotherapy is a low financial cost and the absence of side effects. The potential disadvantage is uncertainty regarding efficacy in treating LUTS. It is possible that phytotherapy is no better than placebo in these men. The National Institutes of Health is planning a national, multicenter clinical trial to determine if phytotherapeutic agents have long-term or short-term efficacy in the management of enlarged prostate.

Invasive therapy.

For men with larger prostates, bothersome symptoms, or other conditions, such as urinary retention, gross hematuria, or bladder stones, invasive therapy may be recommended.^11,17 Minimally invasive therapies include options such as transurethral microwave therapy (TUMT) and transurethral needle ablation (TUNA). These treatment options have a lower total cost, shorter recovery time, and decreased morbidity risk compared with prostate surgery. Although there is a risk of short-term adverse events, such as hematuria, urinary tract infections, irritative voiding symptoms, and urinary retention, the risk of urethral stricture, bladder neck contracture, sexual dysfunction, or urinary incontinence is minimal.¹¹ The AUA guidelines note that the minimally invasive therapies are generally less effective than prostate surgery at improving urinary symptoms and flow rate.¹¹

Surgical therapy, including TURP, transurethral incision of the prostate, transurethral electrovaporization, laser vaporization, and open prostatectomy, is appropriate for men with moderate-to-severe LUTS or for men with enlarged prostate-related complications. In addition to the risk of short-term and long-term complications with invasive procedures, surgical interventions typically cost more than minimally invasive procedures. ¹⁹ Unlike TUMT and TUNA, more invasive surgery, such as TURP, requires general or spinal anesthesia and must be done on an inpatient basis.¹⁹ Even so, TURP is still considered the gold standard for surgical management of enlarged prostate because of its superior treatment outcomes. Prostate surgery has greater efficacy than medical management or minimally invasive options in symptom relief, peak urinary flow rate improvement, and re-treatment rates, but has a higher risk of complications and adverse events.¹¹

Challenges for Managed Care: Is Enlarged Prostate a Hidden Condition?

Diagnosis and management of enlarged prostate is challenging for several reasons, one of which is the reluctance of some men to seek care for this problem. Because men develop LUTS from an enlarged prostate, many attribute it to getting older or are concerned that it may represent prostate cancer or another serious disease process. As men become more aware of this condition, it is likely that there will be increasing numbers of men presenting to their physician for evaluation and management.

Demographics also present a challenge to the managed care industry in the management of enlarged prostate. Because the number of men =65 years of age is projected to increase from 17 million in 2010 to more than 30 million by 2030 (Figure), it is likely that the demand for treatment of enlarged prostate will continue to increase. In addition, because a subset of men with enlarged prostate are at risk for progression to retention or prostate surgery and the ensuing costs that come from these problems, the impact of enlarged prostate on the overall cost of healthcare in the United States is likely to increase.

Opportunities for Managed Care

Given the likelihood that the number of men presenting for treatment of BPH and LUTS will increase, there are potential opportunities for managing this patient group in a cost-effective manner. The Medicare prescription drug plan will potentially increase men's access to prescription drugs for prostate enlargement and other disease processes. Recent data from clinical trials indicating that the risk of progression to retention and surgery can be lowered with 5- alpha reductase inhibitors may provide the opportunity for a decrease in these costs, if this drug class is used in appropriate men requiring medical management of their enlarged prostate.

SUMMARY

The majority of men older than the age of 50 have some degree of prostate enlargement. This condition is often progressive and can lead to bothersome LUTS. A subset of men with enlarged prostate and LUTS are at risk for disease progression to episodes of AUR or prostate surgery. These events can require hospitalization and lead to a significant financial cost for treatment.

Some men who have LUTS and enlarged prostate are reluctant to discuss these problems with their physicians or other healthcare providers because of a general misunderstanding of what they may or may not represent. As patient education continues via the Internet and the information revolution, it is likely that more men will present for treatment of these problems. Additionally, demographics indicate that as the number of elderly men grows over time, there will be an increase in the demand for treatment of LUTS and enlarged prostate.

It is likely that prostate enlargement is going to represent a larger proportion of healthcare costs over the next decade. Because medical management can provide excellent relief of LUTS and also lower the risks of disease progression, there is an opportunity for the management of patients with enlarged prostate to be done in a clinically effective and cost-efficient manner.

Address correspondence to: Michael James Naslund, MD, MBA, The Maryland Prostate Center, 419 W. Redwood St, Suite 320, Baltimore, MD 21201. E-mail: mnaslund@small.umaryland.edu.

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