AUA Guidelines and Their Impact on the Management of BPH: An Update

TREATMENT OF LUTS AND BPH AUA Guidelines and Their Impact on the Management of BPH: An Update Steven A. Kaplan, MD Department of Urology, College of Physicians and Surgeons, Columbia University, New York, NY In 1994, the Benign Prostatic Hyperplasia (BPH) Guidelines Panel published recommendations for the diagnosis and treatment of BPH. However, numerous clinical studies occurring after 1994 led to the development of new medical and surgical therapies. Therefore, the American Urological Association published a more relevant set of guidelines in 2003 detailing this new information. Reviewing BPH literature from before and after 1994, along with unpublished data, led to the publication of new guidelines that reported minimally modified diagnosis methods as well as the updated treatment options for patients with modest to severe and bothersome lower urinary tract symptoms associated with BPH. [Rev Urol. 2004;6(suppl 9):S46-S52] © 2004 MedReviews, LLC Key words: Benign prostatic hyperplasia • Guidelines • American Urological Association • Symptom score • Medical treatment he use of evidence-based guidelines is not unique to urology or to the management of benign prostatic hyperplasia (BPH). In the 1990s, under the aegis of the United States Department of Health Care Policy and Research (AHCPR), the Benign Prostatic Hyperplasia Guidelines Panel published recommendations on both the diagnosis and treatment of BPH.1 The multidisciplinary, 13member, private-sector panel based the guidelines on a review of available literature (1200 abstracts and 200 articles) on BPH. The standard for treatment selection T S46ººººVOL. 6 SUPPL. 9ºº2004ººººREVIEWS IN UROLOGY AUA Guidelines and BPH recommended in the guidelines was that patients consult with physicians and decide on a treatment based on likely outcomes.2,3 The BPH guidelines were released at a press conference in Washington, DC, and received widespread national coverage. This included a video news release produced by the American Association of Retired Persons that was sent by satellite and was carried by 35 television stations and seen by 2.7 million viewers. In addition, the guidelines were distributed extensively through professional journals. To date, the AHCPR has distributed more than 600,000 copies to both providers and consumers, including bulk mailings to hospitals, medical schools, and managed care organizations. Over the past decade, numerous new medical, minimally invasive, and surgical therapies for BPH have been developed. In fact, most of our current knowledge of BPH therapy is based on various open-label studies and randomized clinical trials performed in the late 1990s. These include landmark medical studies such as the Veterans Affairs (VA) Cooperative Initial Evaluation • History • DRE & focused PE • Urinalysis* • PSA in select patients† Presence of AUA/IPSS Symptom Index Assessment of patient bother Mild Symptoms (AUA/IPSS ≤ 7) or no bothersome symptoms Moderate/Severe Symptoms (AUA/IPSS ≥ 8) Optional Diagnostic Tests • Refractory retention or any of the following clearly related to BPH • Persistent gross hematuria‡ • Bladder stones‡ • Recurrent UTIs‡ • Renal insufficiency • Uroflow • PVR Discussion of Treatment Options Patient Chooses Noninvasive Therapy Surgery Patient Chooses Invasive Therapy Optional Diagnostic Tests§ • Pressure flow • Urethrocystoscopy • Prostate ultrasound Watchful Waiting Medical Therapy Minimally Invasive Therapies Surgery Figure 1. Algorithm for benign prostatic hyperplasia (BPH) diagnosis and treatment. *In patients with clinically significant prostatic bleeding, a course of a 5
-reductase inhibitor may be used. If bleeding persists, tissue ablative surgery is indicated. †Patients with at least a 10-year life expectancy for whom knowledge of the presence of prostate cancer would change management or patients for whom the PSA measurement may change the management of voiding symptoms. ‡After exhausting other therapeutic options as discussed in detail in the text. §Some diagnostic tests are used in predicting response to therapy. Pressure-flow studies are most useful in men prior to surgery. AUA, American Urological Association; DRE, digital rectal examination; IPSS, International Prostate Symptom Score; PE, physical examination; PSA, prostate-specific antigen; PVR, postvoid residual urine; UTI, urinary tract infection. Reproduced with permission from American Urological Association Education and Research, Inc.9 Study, Proscar Long-term Efficacy and Safety Study (PLESS), Prospective European Doxazosin and Combination Therapy (PREDICT) study, and Medical Therapy of Prostatic Symptoms (MTOPS) study.4-6 Moreover, minimally invasive therapies such as transurethral microwave thermotherapy (TUMT), transurethral needle ablation of the prostate (TUNA), and interstitial laser coagulation of the prostate have had a renaissance during the last decade. Finally, modification of the most common surgical procedure to treat BPH, ie, transurethral resection of the prostate (TURP), using electrovaporization and the holmium laser, were unknown at the time of the first iteration of the guidelines.7,8 In response, the American Urological Association (AUA) Guidelines Committee selected a panel to update the guidelines. The committee sought input from numerous sources including internists, surgeons, family physicians, and urologists. Both versions of the guidelines were the culmination of an exhaustive effort predicated on using scientifically accepted methods of reviewing medical literature. Moreover, a metaanalysis of all available outcomes data formed the basis of the document. An important role played by the panel members was to fill in gaps. For instance, where there was little evidence-based medicine or conflicting information, the consensus of the panel members was used to support the recommendations. Recommendation terms that quickly became part of the urologic treatment vernacular included “standard,” that which must be done in all cases; “guideline,” that which should be done in most cases; and “option,” that which may be done although clear evidence of its clinical utility is unknown.9 A major breakthrough of the guidelines was that urologists began discussing risks and benefits of various VOL. 6 SUPPL. 9ºº2004ººººREVIEWS IN UROLOGYººººS47 AUA Guidelines and BPH continued treatment algorithms with their patients prior to making a treatment decision.10 This was particularly relevant in quality-of-life disorders such as lower urinary tract symptoms (LUTS) secondary to BPH, urinary incontinence, and sexual dysfunction. The approach to BPH therapy evolved as well. In particular, the importance of BPH progression, how to define it, how to follow it, and how to treat it were considered and became the mainstay of both epidemiologic and clinical studies in the 1990s. In the AUA iteration of the guidelines, the multidisciplinary panel reviewed results of new meta-analyses of BPH outcomes data from before and after 1994. To make the new guidelines as timely as possible, unpublished data were also analyzed by an AUA contracted statistician, discussed extensively by the panel, and incorporated into the guidelines. Studies that were subsequently published included those on the value of combination medical therapy for BPH, such as the PREDICT study and the MTOPS study.5,6,11 The panel updated recommendations for the treatment of LUTS and BPH. In addition, diagnostic algorithms were modified. The following presents highlights of both the updated diagnostic and therapeutic sions about disease management based on an understanding of the risks and benefits of available therapeutic options. Diagnostic Recommendations In essence, the major differences between the 2 published guidelines Almost 85% of men with medically treated BPH are pleased with their choice when surveyed 1 year after treatment commencement. reflect changes in our understanding of the biology of the prostate as well as changes in available treatments. The AUA Guidelines Committee now recommends a urinalysis, serum prostate-specific antigen (PSA) level measurement, and completion of a validated symptom index in the initial evaluation (Figure 1). Serum PSA level determination is recommended for men with a life expectancy of 10 years or longer and for those whose PSA level may influence BPH treatment. This includes most patients who are considering treatment with a 5
reductase inhibitor (5ARI). Prostatespecific antigen level is a useful surrogate marker for prostate size and can also be used to predict future prostate growth and risk for urinary retention or surgery.12-14 Measurement of serum A major breakthrough of the guidelines was that urologists began discussing risks and benefits of various treatment algorithms with their patients prior to making a treatment decision. algorithms and discusses how these recommendations for evaluation and treatment have evolved since 1994. Similar to that in the 1994 published guidelines, the intent of the 2003 guidelines was to provide evidencebased data on treatment outcomes so that physicians can assist their patients in making appropriate deci- Score) should be used as the symptom-scoring instrument in the initial assessment of patients presenting with BPH.15-18 American Urological Association symptom scores (AUASSs) of 0-7 are classified as mild, 8-19 as moderate, and 20-35 as severe LUTS. It is suggested that patients creatinine is no longer routinely recommended as multiple, long-term, placebo-controlled trials have shown that the incidence of renal insufficiency in men with BPH is the same as in the general population. The AUA Symptom Index (identical to the 7 symptom questions of the International Prostate Symptom S48ººººVOL. 6 SUPPL. 9ºº2004ººººREVIEWS IN UROLOGY with mild symptoms (AUA-SS ≤ 7) and patients with moderate or severe symptoms (AUA-SS ≥ 8) who are not bothered by their symptoms (ie, symptoms do not interfere with daily activities) should be managed using a strategy of watchful waiting. Usually patients with mild to severe symptoms that are not bothersome prefer watchful waiting, although there is a wide range of patients with bothersome moderate to severe symptoms who prefer this strategy as well. In general, most patients will undergo medical management prior to any form of surgical intervention. Surgical intervention includes TURP, transurethral incision of the prostate, open prostatectomy, or minimally invasive therapies such as heat therapies for the prostate (most commonly transurethral microwave thermotherapy, transurethral needle ablation, and water-induced thermotherapy). When counseled about treatment options and potential complications, most patients prefer less invasive treatments. In fact, almost 85% of men with medically treated BPH are pleased with their conservative choice when surveyed 1 year later. Today, BPH can be treated medically with new therapies such as phytotherapy,
-blockers, and 5ARIs. Another major change since 1994 concerns indications for surgical inter- AUA Guidelines and BPH Watchful Waiting A significant proportion of men with LUTS will not elect medical or surgical intervention. Reasons for this include: • non-bothersome symptoms • the perception that the complications of treatment are greater than the inconvenience of the symptoms • the reluctance to take a daily pill due to unrecognized long-term side effects, and/or the cost of treatment. In addition, the progression of BPH is generally slow and unpredictable, and not all patients experience increasing symptoms, even if objective measurements such as peak flow rates continue to decline. Watchful waiting does not imply total absence of intervention, however. Severity and bother due to LUTS may be improved by decreasing total fluid intake, moderating the intake of alcohol- and caffeine-containing products, limiting the use of salt and spices, and maintaining timed voiding schedules.10,15,17,19 The impact of watchful waiting was examined in a study of 556 men randomized to either surgery or watchful waiting. There were twice as many treatment failures in the watchful waiting group. Of these patients, 24% underwent surgery during the 3-year study period, with one third due to persistent symptoms. Data stratified by preoperative symptom scores revealed that patients with mild to moderate symptom scores in the watchful waiting group underwent TURP less frequently than those with high preoperative symptom scores. Table 1 Treatment Options for Patients With Moderate to Severe Symptoms of Benign Prostatic Hyperplasia Watchful waiting Medical therapies •
-Adrenergic blockers • Alfuzosin • Doxazosin • Tamsulosin • Terazosin • 5
-Reductase inhibitors • Dutasteride* • Finasteride • Combination therapy (
-blocker and 5
-reductase inhibitor)* † Minimally invasive therapies • Transurethral microwave heat treatments • CoreThermTM* • Prostatron® (various versions) • Targis® • TherMatrx®* • Transurethral needle ablation • UroLume® stent‡ Surgical therapies • Transurethral resection of the prostate • Transurethral electrovaporization • Transurethral incision of the prostate • Transurethral holmium laser resection/enucleation • Transurethral laser vaporization • Transurethral laser coagulation (eg, visual laser ablation) • Open prostatectomy *Recommendations based on randomized, controlled trials not included in the outcomes tables. †The panel assumes that the combination of any effective
-blocker and 5
-reductase inhibitor probably produces a comparable benefit. However, the best-tested combination is doxazosin and finasteride. The safety of specific combinations other than finasteride plus doxazosin, terazosin, and alfuzosin has not been assessed. ‡ Not for patients with poor surgical risk. Reproduced with permission from American Urological Association Education and Research, Inc.9 vention. Patients with gross hematuria were routinely treated by surgery in the past. Today, they are offered treatment with a 5ARI such as finasteride or dutasteride.19 Urinary retention is treated with the concomitant use of an in-dwelling catheter and an
-blocker such as alfuzosin or tamsulosin. Then a trial without catheter is instituted. Therapeutic Recommendations The panel chose a number of recommended treatment options for patients with moderate to severe and bothersome LUTS associated with BPH (Table 1). Phytotherapy Phytotherapies for BPH are becoming increasingly popular, and although many physicians remain skeptical of their value, patients seem generally satisfied with their use. Two of the more common herbal medications VOL. 6 SUPPL. 9ºº2004ººººREVIEWS IN UROLOGYººººS49 AUA Guidelines and BPH continued taken include Serenoa repens (saw palmetto berry) and Pygeum africanum (red stinkwood or African plum). Meta-analysis of the randomized trials using saw palmetto showed that in the short term (average 9 weeks), improvements in symptoms (AUA-SS 1.4 points) and flow rates (1.93 mL/sec) approached those in patients taking finasteride.20,21 Constituents include flavonoids, ß-sitosterol, campesterol, and stigmasterol. These ingredients reduce swelling and inflammation and appear to naturally inhibit both Type 1 and Type 2 5
-reductase (5AR) and to block dihydrotestosterone (DHT) from binding to cytosolic androgen receptors in the prostate gland. In the latest meta-analysis of clinical trials using saw palmetto, Boyle and colleagues22 included only those studies using permixon, a standardized lipid-sterolic extract of Serenoa repens manufactured in France. All of the published trials together involved 2859 patients studied for 21 to 180 days. The estimated effect of permixon was an increase of 2.71 mL/sec in peak urinary flow rates (compared with 0.51 mL/sec for placebo). In addition, permixon decreased mean number of nocturnal urinations by 1.19 (compared with 0.69 for placebo). Treatment duration did not influence the magnitude of either of these events.
-Adrenoceptor Antagonists Currently, there are 4
-blockers approved by the US Food and Drug Administration (FDA) to treat LUTS: doxazosin, terazosin, tamsulosin, and alfuzosin.23-30 The AUA Guidelines Committee believes that all 4 are equally effective, causing an average 4- to 6-point improvement in the AUA-SS, which most patients perceive as a meaningful change. Adverse side effects commonly reported with different
1-blockers include dizziness, headache, asthenia, postural hypotension, rhinitis, and sexual dysfunction, most commonly occurring in about 5% to 9% of patient populations.9 5
-Reductase Inhibitors The 2003 guidelines recommend 5ARIs as an effective and appropriate option for treating men with enlarged prostates and associated LUTS. The PLESS trial was the largest clinical trial to investigate finasteride for the management of BPH.12-14 In this multicenter, double-blind, placebo-controlled study conducted in the United States, more than 3000 men with in the treatment of BPH. The FDA recently approved a supplemental new drug application for dutasteride for treatment of symptomatic BPH.31 Dutasteride is a second-generation 5ARI that inhibits both Type 1 and 2 5AR. Dutasteride was investigated in 3 large, well-controlled, multicenter studies involving 4325 men 50 years old or older. Data from these 2-year clinical trials demonstrated that treatment with 0.5 mg dutasteride once daily reduced the risk of acute urinary retention and BPH more than placebo, Data from 2-year clinical trials demonstrated that treatment with 0.5 mg dutasteride once daily reduced the risk of acute urinary retention and BPH more than placebo. moderate to severe urinary symptoms and an enlarged prostate at baseline were randomized to finasteride 5 mg/day or placebo. During the 4-year study period, 152 (10%) of the 1516 men in the placebo group and 69 (5%) of the 1524 men in the finasteride group underwent surgery for BPH (reduction in risk with finasteride 55%). Acute urinary retention developed in 99 (7%) men in the placebo group and 42 (3%) in the finasteride group (reduction in risk 57%). Among men who completed the study, mean decreases in symptom scores were 3.3 in the finasteride group and 1.3 in the placebo group (P < .001). Treatment with finasteride improved urinary flow rates and reduced prostate volume (P < .001). This study suggested that long-term medical therapy could impact the natural history of BPH as manifested by acute urinary retention and surgery. Moreover, the degree of symptomatic improvement in those who responded appeared to be equal to that of patients on
-blockade. Investigators have hypothesized that inhibition of both Types 1 and 2 5AR demonstrate increased efficacy S50ººººVOL. 6 SUPPL. 9ºº2004ººººREVIEWS IN UROLOGY improved BPH-related symptoms, decreased prostate volume, and increased maximum urinary flow rates. Finasteride and dutasteride suppress DHT production by 70% and 93%, respectively, although their objective and subjective effects are similar. Data from the 2-year extension phase of the dutasteride trials indicate a durable benefit at 48 months for men with symptomatic BPH. Sustained improvements were evident in DHT suppression, total prostate volume, symptoms, and urinary flow. Risk of AUR- or BPH-related surgery was also durable at year 4. The dutasteride-treated patients experienced an average reduction in AUASI scores of 4.4 points at month 24 and 6.5 points by month 48. Combination Therapy The initial experience with combining
-blocker and 5AR therapy was not promising. In a VA Cooperative Group study, 1 year of combination therapy was no more effective than monotherapy in improving symptoms or flow rates and substantially increased the cost of treatment. AUA Guidelines and BPH The recently published MTOPS study has changed the thinking regarding combination therapy, however. More than 3000 men were randomized to receive either placebo, doxazosin (
-blocker), finasteride (5ARI), or both.5,6 The principal outcome that followed was clinical progression—defined as either an increase agents was not. Combination therapy caused a 66% risk reduction of clinical progression compared with placebo, which was significantly different from the other 3 arms. These results demonstrated the value of combination therapy in the treatment of BPH and provided the foundation for an international clin- Combination therapy caused a 66% risk reduction of clinical progression compared with placebo. of at least 4 points in AUA-SS, or urinary retention, incontinence, renal insufficiency, or recurrent urinary tract infection. Other dependent variables included maximal urinary flow rate, serum PSA level, and incidence of invasive therapy. After a median 4.5 years of follow-up, the median change in AUA-SS was –4 for placebo, –6 for doxazosin, –5 for finasteride, and –7 for combination therapy. All differences were statistically significant. Clinical progression, which was mostly due to increasing AUA-SS, occurred in 4.5 per 100 patients per year in the placebo group. Doxazosin and finasteride reduced the risk of progression by 39% and 34%, respectively, and although the difference between the 2 agents and placebo was significantly different, the difference between the 2 ical trial of the safety and efficacy of dutasteride and tamsulosin, alone or in combination, for men with symptomatic BPH. This 4-year randomized study (COMBAT, Combination of AvodartTM [dutasteride] and tamsulosin) will enroll approximately 4500 men from the United States and Europe age 50 years or more and is expected to elucidate the long-term effects of combination therapy for men with symptomatic BPH at high risk of disease progression. Endpoints include improved urinary symptoms after 2 years and reduced risk of progression (acute urinary retention and BPHrelated surgery) at 4 years. Minimally Invasive Therapies Of the minimally invasive therapies, the panel recommends 4 transurethral microwave heat treatments as options, namely the CoreTherm® device (Prostalund Operations AB, Lund, Sweden), the Prostatron® device (EDAP Technomed, Inc., Lyon, France) in different software versions, the TARGIS® device (Urologix, Inc., Minneapolis, MN), and the TherMatrx® device (TherMatrx, Inc., Northbrook, IL). All of these devices are high energy except for CoreTherm. The TARGIS and Prostatron devices feature water cooling, whereas the TherMatrx device uses an intraprostatic needle to report temperature within the prostate and thereby individualizes the treatment. Despite these differences, the panel concluded that there is no superiority of one transurethral microwave heat treatment over another. However, the FDA noted that a number of patients treated by cooled thermotherapy had significant complications including fistula and penile necrosis. This underscores the need for physicians to be in attendance when these treatments are administered. Other minimally invasive therapies recommended as treatment options are the transurethral needle ablation by radiofrequency energy and the UroLume® stent (American Medical Systems, Inc., Minnetonka, MN), the only mechanical device to maintain patency of the prostatic urethra. The stent, however, is not recommended for typical patients, but for patients at poor surgical risk. Other therapies such as injection Main Points • Since the first guidelines on benign prostatic hyperplasia (BPH) published in 1994, numerous new minimally invasive and surgical therapies have been developed, prompting the American Urological Association (AUA) to publish an updated version of the guidelines in 2003. • The second iteration of the guidelines differed from the first in that it reviewed BPH literature from before and after 1994 as well as unpublished data. It reflects changes in our understanding of the biology of the prostate and changes in available treatments. • During initial evaluation, the new AUA guidelines recommend that physicians perform a urinalysis, obtain the patient’s serum prostate-specific antigen level, and ask the patient to complete a validated symptom index in order to determine the appropriate treatment option. • The AUA Guidelines Committee recommends a number of treatment options for patients with modest-to-severe and bothersome lower urinary tract symptoms associated with BPH including watchful waiting, phytotherapy,
-adrenoceptor antagonists, 5
-reductase inhibitors (5ARIs), combination therapy with an
-blocker and 5ARI, and transurethral microwave heat treatments. VOL. 6 SUPPL. 9ºº2004ººººREVIEWS IN UROLOGYººººS51 AUA Guidelines and BPH continued of absolute ethanol into the prostate, high-intensity focused ultrasound, certain other transurethral heatbased therapies (interstitial laser coagulation and water-induced thermotherapy), and the Plasma Kinetic™ Tissue Management System are listed as emerging therapies. Other therapies formally recommended as treatment options include lasers, specifically, the transurethral holmium laser resection, which are used to either resect or vaporize the prostate. Conclusions The evolution of medicine is constant but has become a challenge as meta-analyses and extensive reviews of published and unpublished data sets are impossible on a daily basis but necessary to develop the guidelines that will lead to new therapeutic recommendations. New research on the biology of prostate disease and novel therapeutic targets is underway, it is likely that the impact will not be evident until after the next decade. It is expected, however, that current National Institutes of Health trials involving minimally invasive therapies and phytotherapeutic agents will provide greater insight into these therapies in the near future. Acknowledging that new research results are usually accompanied by new insights and new questions, the Guidelines committee outlined future directions and priorities for clinical research activities and presented a blueprint for better reporting and publication of research results. As more results from long-term combination trials are published and lay the foundation for other large-scale, long-term, combination trials there may be a shift in focus for the patient and his physician from treating symptoms alone to preventing disease progression and/or complications. 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