Optimal Management of BPH – Family MD stream

Pre/post test1. Do approximately 90% of men between the ages of 45 and 80 years suffer from some type of lower

urinary tract symptom (LUTS)?a. Yesb. No

2. Is testosterone the main culprit for the development of Benign Prostatic Hypertrophy (BPH)?a. Yesb. No

3. Does the size of the prostate correlate with the severity of LUTS?a. Yesb. No

4. Is urgency, frequency and urge incontinence considered storage lower urinary tract symptoms (LUTS)?

a. Yesb. No

5. Do most men with lower urinary tract symptoms discuss their symptoms with their primary care physician?

a. Yesb. No

6. Is the digital rectal exam a mandatory component for diagnosing BPH?a. Yesb. No

7. Does PSA have a role in the assessment of selected patients with BPH?a. Yesb. No

8. Should watchful waiting for at least 3 months be the first treatment option for all patients with BPH?a. Yesb. No

9. Is combination therapy with an alpha blocker and 5 alpha-reductase inhibitor more effective than either therapy alone?

a. Yesb. No

10. Is saw palmetto a recommended option for the treatment of BPH?a. Yesb. No

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Pre-Course Survey1. How comfortable do you feel assessing lower urinary tract symptoms in men over the age of 50? (1=

not at all comfortable, 5 = very comfortable)2. How would you rate your ability to diagnose benign prostatic hyperplasia based on current best

practice guidelines? (1 Diagnose with significant difficulty, 5 Diagnose with ease)3. How comfortable do you feel selecting the most appropriate BPH treatment based on current

clinical practice guidelines? (1 not at all comfortable, 5 very comfortable)4. How comfortable do you feel discussing the pros and cons of each BPH treatment option with your

patients? (1 not at all comfortable, 5 very comfortable)5. How would you rate your proficiency on the complete management of your patients with BPH? (1=

low, 5 = very high)

Meet our Patient Robert S. (64 years old) is in your office to discuss his lower urinary tract symptoms (LUTS). When you review his chart you see the following notes:

Robert S. 64 years old

Current Medications Perindopril 4 mg daily Amlodipine 5 mg daily

Urology Specific notes: Presented with LUTS symptoms

approximately 3 months ago Today’s IPSS score of 17

o Storage and voiding symptomso QOL score is 5

Last PSA = 2.4 ng/mL Urinalysis normal DRE 3 months Ago– Moderate

enlargement, smooth, non-tender prostate

No family history of prostate cancer Both father and older brother have

had LUTS associated with BPH

Case Challenge1. Which of the following is the MOST appropriate action for this patient?

a. Do nothing he has little bother from symptoms so no treatment is indicatedb. Discuss bother, BPH and different treatment options

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c. Refer to urologist to rule out prostate cancerd. Refer to urologist to manage BPH symptoms

2. Should you be worried about his PSA reading?a. Yes, he should be referred to a urologist for a prostate cancer assessmentb. No, his reading is not high, he has no risk factors for prostate cancer and is most likely

associated with BPH

Introduction Lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) are commonly seen in clinical practice. One internet survey of US, UK and Swedish patients ≥ 40 years of age found that close to 71% of men had at least one LUTS and about half reported LUTS from multiple symptom groups (voiding, storage or postmicturition).1 Another study estimated that 90% of men between 45 and 80 years of age suffer from some type of LUTS.2 Benign prostatic hyperplasia (BPH) is the primary cause of lower urinary tract symptoms (LUTS) in older men. It affects: 3

Approximately 42% of men aged 51-60 years Over 70% of men 61-70 years Almost 90% of men aged 81 to 90.

With BPH affecting such a large portion of men, it is important that each clinician feel comfortable with the evidence based management of the condition. Primary care physicians are ideally placed for case detection of BPH, patient assessment and initiating management strategies.

Learning ObjectivesUpon successful completion of this program the physician will be better able to:

1. Implement the evidence based assessment and diagnosis of LUTS secondary benign prostatic hyperplasia (BPH) in clinical practice

2. Describe the impact of BPH LUTS on the quality of life of patients, and the role of treatment in symptom improvement and disease progression

3. Prescribe and tailor treatment options for patients based on BPH symptoms4. Discuss the level of evidence to support each treatment option for BPH symptoms5. Discuss appropriate follow-up and shared BPH care between family physicians and urologists

Benign Prostatic HyperplasiaBenign prostatic hyperplasia (BPH) is defined as a histologic diagnosis that refers to the proliferation of smooth muscle and epithelial cells within the prostatic transition zone.2 This hyperplasia occurs in

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Clinical Practice TipsBPH associated LUTS is seen in over 50% of men over 50 years old

nodular compression, primarily in the transitional zone of the prostate.4 This leads to prostate gland enlargement which may cause lower urinary tract symptoms (LUTS).

Etiology of BPHThe exact cause of BPH is unknown, but is thought to be primarily hormonal based.3 The testes are crucial in the development of BPH, where castrated men (surgically or chemically) do not develop BPH.4 Testosterone itself is not thought to be the culprit hormone to BPH development but rather the hormone dihydrotestosterone (DHT).4 This hormone is produced through the conversion of testosterone by the enzyme 5 alpha-reductase type 2 in the stromal cells of the prostate.4 Here are some key facts regarding DHT:4

DHT is mainly synthesized in the prostate In the serum, the testosterone level is higher than DHT (ratio testosterone:DHT > 10). The ratio

is reversed in the prostate DHT binds more tightly to the androgen receptors in the stromal cells than testosterone Testosterone levels decrease as a man ages but DHT levels do not, thus leading to the altered

cell growth dynamics in the prostate DHT and the enzyme 5 alpha-reductase are crucial to the continual hyperplasia in the prostate

Risk factors for BPHFamily history of BPH and increasing age are thought to be the primary risk factor for the development of BPH.3 Sexual activity and alcohol have not proven to contribute to BPH development.3 Certain races such as people of African descent were thought to be at significant risk for the development of BPH but several trials question African race as a risk factor for BPH.5,6

There is increasing research on the role of metabolic syndrome risk factors and the development of BPH. A review of evidence suggests that diabetes, hypertension, ischemic heart disease, insulin resistance and dyslipidemia are possible risk factors for BPH.7 In the recent American Urological Association (AUA) BPH guidelines the possible link between obesity, metabolic syndrome and BPH was viewed as a high priority for future research.2

Symptoms of BPHThe growth of the prostatic tissue starts to compress the prostatic urethra. This compression leads to the development of many of the lower urinary tract symptoms (LUTS) associated with the condition. LUTS include storage and/or voiding disturbances are common in aging men.

Storage symptoms are experienced during the storage phase of the bladder and include daytime frequency and nocturia.2

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Clinical Practice Tip:The size of the prostate does not correlate well to the severity of BPH symptoms.1 One study demonstrated of patients diagnosed with BPH symptoms: 8

24.3% had large size prostates 50% had medium size prostates 25.7% had small size prostates.

Voiding symptoms are experienced during the voiding phase (e.g. urinary hesitancy, slow stream).2

Approximately one half of patients with BPH experience LUTS, of which urinary hesitancy, weak stream and nocturia are the most common symptoms.3 Table 1 lists the most common storage and voiding LUTS of BPH. 8

BPH is a progressive condition BPH may progress in the form of increased prostate volume, reduction in maximum urinary flow rate and increased risk of acute urinary retention and surgery.9

Table 1 – Lower Urinary Tract Symptoms (LUTS) seen in benign prostatic hyperplasia3

Storage Voiding Other Urgency Frequency Nocturia Urge incontinence

Hesitancy Poor flow Intermittency Straining Dysuria (painful

urination) Incomplete emptying

Postvoid dribble

Patient Perceptions of BPH Most cases of BPH are asymptomatic. Among those with symptoms, many men will not seek treatment for the symptoms of BPH, even though their symptoms are often moderate to severe and lead to a decrease in the quality of life, anxiety and depression.10 One study evaluated the reasons for not discussing their symptoms with their physician.11 This survey found that 39% of men did not seek treatment from their doctor, despite having moderate to severe BPH.11 Fear of prostate cancer, the severity of symptoms, bother, interference with activities, and decreased quality of life are the main reasons men will seek treatment for BPH.

Some of the reasons that men with symptoms cite for not seeking care include:11

Acceptance that LUTS are a natural part of aging Symptoms are not causing significant bother Stigma associated with symptoms such as dribbling and urgency Fear of cancer or surgery and its associated side effects.

Among patients who consulted their family physician, their LUTS were the main reason to initiate the discussion, but several other factors were much more likely to motivate a patient to seek treatment:11

Social influences including being advised by others (e.g. spouse) to see a doctor (odds ratio (OR) = 5.5)

Belief that the physician could improve their condition (OR =2.7) Information in the mass media about symptoms (OR = 2.1)

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Clinical Practice Tip:Close to 40% of men with LUTS do not seek treatment. This underscores the need for active case detection by family physicians.

Case detection of LUTS is an important component to diagnosing and management of BPH. All men over the age of 50 years should be screened for LUTS by asking the one question (or similar screening questions)in figure 1 during a physical exam or system review.10

If the patient answers no to any problems urinating, then no further questioning or assessment is required. If the patient answers yes, then the clinician is encouraged to investigate further (see next section). Through appropriate questioning, clinicians can help identify patients that have significant symptoms but fail to initiate the discussion with their family physician regarding their LUTS.

Figure 1 – Case Detection Question for LUTS and BPH

* - Urinating can be replaced with any of the following terms depending on the patient: peeing, voiding or passing water

Case ChallengeYou mention to Robert that you think he has BPH. You decide to run through a full a diagnostic evaluation for BPH.

1. Which of the following test is mandatory for the diagnosis of BPH?a. Urinalysisb. IPSS completionc. PSAd. Serum creatinine

2. Which of the following symptoms would suggest a referral to an urologist is appropriate?a. Medium size prostateb. Any PSA level > 2.0 ng/mLc. Previous urological surgery

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d. All of the above3. When treating BPH which of the following plays the largest factor in determining the need for

treatment?a. PSA scoreb. IPSS/AUA-SI scorec. Patient’s level of botherd. Prostate size

Diagnostic EvaluationCurrent Canadian, American and Australian clinical practice guidelines recommend physicians tailor their assessment based on mandatory and optional testing. The mandatory tests for all men with LUTS include a patient history, physical exam, urinalysis and a recommended test that could be performed in selected men with LUTS is serum PSA. 12 Mandatory and Recommended Tests

Patient HistoryA medical history should be performed to clearly establish the symptoms and exclude other conditions.3 A focussed patient history should be obtained. Table 2 lists some areas to focus upon when conducting a medical history. Table 3 lists other conditions that could be causing LUTS. Table 4 lists medications that could be contributing to LUTS.

Table 2 – Suggested areas for clinicians to assess when conducting a patient history12,13

Previous surgical procedures (especially any urological procedures) Any previous trauma to the genitourinary tract Sexual function history Medications currently taken Family history of BPH and prostate cancer

Table 3 – Differential diagnosis of LUTS3 Bladder cancer Prostate cancer Prostatitis Bladder stones Interstitial cystitis Radiation cystitis Urinary tract infection

Diabetes mellitus Parkinson’s disease Primary bladder neck hypertrophy Congestive heart failure Lumbosacral disc disease Multiple sclerosis Nocturnal polyuria

Table 4 - Medications that may Contribute to Lower Urinary Tract Symptoms3

Medications NotesAntihistamines Decreased parasympathetic toneDecongestants Increased sphincter tone via alpha-adrenergic receptor stimulationDiuretics Increased urine productionOpiates Impaired bladder contractilityTricyclic Antidepressants Anticholinergic effects

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Assessment of LUTS and Symptom BotherOne of the most important components of the patient history is the assessment of the type, severity and duration of LUTS. The International Prostate Symptom Score (IPSS) and the American Urological Association Symptom Index (AUA-SI) are tools that can aid in the evaluation and quantification of a patient’s symptom severity.3 Table 5 lists the IPSS.

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Clinical Practice Tip:From a clinical practice standpoint the IPSS tools is an appropriate method to assess and quantify symptom severity and quality of life impact

Table 5 – International Prostate Symptom Score (IPSS)

QuestionNot at

allLess than 1 time in

5

Less than half the

time

About half the time

More than half the time

Almost always

Incomplete Emptying1. Over the past month, how often have you had a

sensation of not emptying your bladder completely after you finish urinating? (S)

0 1 2 3 4 5

Frequency2. Over the past month, how often have you had to

urinate again less than two hours after you finished urinating? (S)

0 1 2 3 4 5

Intermittency3. Over the past month, how often have you found

you stopped and started again several times when you urinated? (V)

0 1 2 3 4 5

Urgency4. Over the last month, how difficult have you found

it to postpone urination? (S)0 1 2 3 4 5

Weak Stream5. Over the past month, how often have you had a

weak urinary stream? (V)0 1 2 3 4 5

Straining 6. Over the past month, how often have you had to

push or strain to begin urination? (V)0 1 2 3 4 5

None 1 time 2 times 3 times 4 times 5 or more times

Nocturia7. Over the past month, many times did you most

typically get up to urinate from the time you went to bed until the time you got up in the morning? (S)

0 1 2 3 4 5

Total Symptom Score:_____ Score 0-7 = Mild Score 8-19 = Moderate Score 20-35=Severe

Quality of life AssessmentIf you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that?(scored on a scale of 0 to 6 points (delighted to terrible)(S) – Storage symptoms; (V) – Voiding symptoms

The IPSS is an excellent tool to assess symptom severity, and the impact of symptoms on a patient’s quality of life. Clinicians should also assess the level of bother of the symptoms by asking a question such as:

“On a scale from 1 to 5 how would you rate how bothersome your symptoms are? Where 1 is for not bothersome at all and 5 is for bothers me a lot”

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Clinical Practice Tip:Many clinicians do not use formal surveys in their practice. The IPSS can be used as a guide of questions to ask your patients.

It is important to at least assess: Severity, frequency of voiding and storage

LUTS The impact of these symptoms on the patient

From a clinical practice standpoint, some of the most important questions are associated with the impact of LUTS on QOL and level of bother of these symptoms. The larger the bother and the greater impact of the symptoms on quality of life, directs clinician to a stronger indication for treatment.

Physical Exam and Digital Rectal Exam (DRE)A focussed physical exam should be performed to assess the suprapubic area to rule out bladder distension and overall motor and sensory function on the perineum and lower limbs.13 Palpitation and percussion of the suprapubic area can be done to determine whether a significant amount of residual urine is present.3 Clinicians are encouraged to exam the external genitalia and testes to rule out meatal stenosis or other anomalies.3 A focussed neurological exam (perianal and perineal sensation and muscle tone) is also recommended.14

Digital Rectal ExamThe DRE is the most important component of the physical exam.3 DRE is used to assess the size, shape, symmetry, quality, nodularity and consistency of the prostate and this can provide evidence if advanced prostate cancer exists.3 A palpable nodule is suggestive of prostate cancer and should be referred to an urologist to determine if a prostate biopsy is required.3 The DRE is a grossly inaccurate method of estimating definitive prostate volume.2 The volumes of small prostates tend to be overestimated and those with large glands tend to be underestimated.2 However, the DRE can provide an indication whether a prostate gland is abnormal or enlarged, the only important considerations in managing BPH/LUTS. Table 7 provides some guidance into methods you can use to classify the size of the prostate.

Table 7 – Quick Guide for Estimating Prostate Gland SizeSmall(<30 cc) Normal

Size of walnut No protrusion into rectum

Medium (30-50 cc) Size of egg Back of prostate is protruding 1-2 cm into the rectum

Large (> 50cc) Size of tangerine More protrusion into the rectum.

Extra-large (> 80 cc) Size of an orange Major protrusion into the rectum It is difficult to feel the entire posterior of the prostate

UrinalysisUrinalysis is necessary to screen for urinary tract infections, bladder cancer and stones.3 Widely available dipsticks can be utilized to test for hematuria, proteinuria, pyuria or other pathological findings (e.g. glucosuria, ketonuria, positive nitrite test, leukocyte exterase, etc.).2 Examination of urinary

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Clinical Practice Tip:Never try to estimate the size of the prostate in mL as it is grossly inaccurate. It is better to classify prostate size in relative terms such as small, medium, large, and extra-large

sediment and culture may be indicated if the results of the dipstick are abnormal.2 Urinalysis results may guide further testing independent of the evaluation of LUTS (e.g. cytology, cystoscopy, imaging).13

Role of Prostate-Specific AntigenProstate-specific antigen (PSA) is a protein produced by cells of the prostate gland. PSA is normally very low in most patients, but will become elevated in patients with BPH and prostatic cancer.

PSA is an established biomarker for prostate cancer but can also be used for the diagnosis of BPH and provides important information on its risk of progression.3 In patients with BPH, serum PSA is a strong predictor of future prostate growth, BPH symptom and urine flow deterioration, acute urinary retention and surgery.3 In some BPH studies, prostate growth rates ranged from 7.4% to 22% over 4 years. Prostate growth was highest for men with the highest baseline PSA levels:15 Table 8 lists the yearly prostate growth based on the baseline PSA values.

Table 8 – Prostate growth based on PSA values15

Baseline PSA Prostate Growth0.2-1.3 ng/mL 0.7 mL/year1.4-3.2 ng/mL 2.1 mL/year3.3-9.9 ng/mL 3.3 mL/year

One study determined that over 4 years, all but one man with PSA> 2.0 ng/mL experienced prostate growth over the 4 years. Increasing PSA is also a risk factor for acute urinary retention and BPH-related surgery.16

PSA ≥ 1.5 ng/mL has been defined as the threshold for which patients with BPH are considered at risk for progressive disease.17 Patients at risk for progression may benefit from medical therapy to treat both disease progression and symptoms, which may be combination therapy with a 5-alpha reductase inhibitor and an alpha blocker.

PSA screening of asymptomatic men for prostate cancer is very controversial. PSA testing initiation has been recommended for most men at the age of 50.3 If the patient has a strong family history of prostate cancer (first-degree relative) or if the patient belongs to a high-risk group (African American males), it has been recommended that testing start at age 40.3 However, the argument for PSA testing in patients with BPH/LUTS is not screening but performed for case detection, progression prediction and therapeutic decision making. A diagnosis of prostate cancer in a man with LUTS will have a direct impact

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Clinical Practice Tip:PSA prostate cancer case detection should only be offered to men with a life expectancy of greater than 10 years and if the diagnosis of prostate cancer would modify the management approach

Clinical Practice Tip: A rising PSA (<0.75 ng/mL/year)

may indicate an increased risk for prostate cancer

A rapid rise to high PSA level may indicate prostatitis

A stable or slowly rising PSA suggests BPH

on treatment decisions, while PSA associated with a benign prostate has important implications in terms of progression risk and choice and timing of therapy.

Specialist ReferralPrimary care physicians are ideally positioned to identify men with LUTS and those at risk of disease progression.3 They should consider providing treatment options for those men with mild to moderate symptoms without evidence of prostate cancer.3 Table 9 lists circumstances where the primary care should consider referring the patient for specialist assessment.

The cases of BPH are likely to increase with our aging population. It is important for primary care physicians to feel comfortable with the diagnosis and initial management of BPH to ensure their patients are achieving optimal and timely treatment.

Table 9 – Circumstances for Primary Care Physicians to Consider Specialist Referral Suspicion of prostate cancer Abnormal DRE Refractory to first-line medical treatment Intolerance to medication Significant progression Recurrent urinary retention Patient who prefer the thought of one-time surgical option versus medical therapy A patient with significant LUTS who is insistent on seeing a urologist Complications present:

o Hematuriao Urinary tract infectiono Hydronephrosis (if found on ultrasound)o Bladder stones

Recurrent urinary infections Renal insufficiency Abnormal PSA level or PSA velocity (e.g. PSA value doubling in last year)

Case Challenge You start reviewing the BPH treatment options with Robert.

1. Which of the following is a consideration when selecting a BPH treatment option for Robert?a. The amount the symptoms are bothering himb. The size of the prostatec. His PSA leveld. All of the above

2. Robert has an IPSS score of 17 (both voiding and storage LUTS), QOL score of 5, and his DRE shows moderate prostate enlargement. Which of the following provides the LEAST long-term benefits?

a. Watchful waitingb. Alpha blockers

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c. 5-alpha reductase inhibitord. Surgical options

Treatment Goals of BPHWith the improvement in treatment options for BPH, the goals of treatment are now being met with pharmacotherapy. Whether the treatment is conservative or aggressive the aims of BPH treatment include:

Improve symptoms and reduce impact/bother Improve urinary flow and bladder emptying Reduce clinical progression of the disease and thereby reducing or delaying the need for surgery

and reducing the risk of acute urinary retention

Basic Management of BPHThe treatment of BPH is based on a combination of the symptoms, the amount the symptoms are bothering the patient and the size of the prostate (PSA can be used as a surrogate marker for prostate size in patients with no clinical evidence of prostate cancer).3 Figure 2 provides a treatment algorithm for BPH.

Treatment options for BPH include “watchful waiting”, pharmacotherapy and surgery. Most of the patients being seen in primary care physician’s offices have mild or no symptoms, but a good percentage, particularly those complaining of LUTS, have moderate to severe symptoms (PSS >8) and enlarged prostates.3 Once the risk of cancer has been ruled out, most can be managed with watchful waiting, while those with bothersome symptoms can be offered either pharmacotherapy or surgery but it is imperative to take the patient’s treatment preference into consideration. The patient may wish to take a different treatment path compared to the clinicians. It is critical the clinician discuss the benefits and risks associated with each treatment option and allow the treatment process be jointly decided between the patient and clinician.3

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Figure 2 – Treatment Algorithm of BPH2,12

* - Patients with predominantly significant polyuria - consider using a frequency volume chart for diagnosis

Polyuria - ≥ 3 litres output in 24 hours – lifestyle and fluid intake to be reduced Nocturnal polyuria - ≥ 33% output at night – fluid intake to be reduced and consider other cause

† - In patients with mild symptoms and mild bother but with a large prostate, the clinician may want to consider a 5-alpha reductase inhibitor to slow the progression of the condition.

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‡ - If a patient has significantly bothersome LUTS, it should be remembered that 5 alpha reductase inhibitor monotherapy may take 3-6 months for full onset of action.

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Watchful Waiting

Current Recommendation: Patients with mild symptoms of LUTS secondary to BPH (IPSS score <8) and patients with

moderate or severe symptoms (IPSS score ≥8) who are not bothered by their LUTS should be managed using a strategy of watchful waiting (active surveillance).2

Patients with mild symptoms and severe bother should undergo further assessment.12

Watchful waiting or “active surveillance” is a strategy where the patient is monitored by their physician but receives no active treatment. This strategy is considered the treatment of choice in patients with mild LUTS (IPSS<8) and minimal bother from their symptoms and with or without a large prostate.3

Self-management of LUTS involves the patient becoming responsible for the day-to-day management of their condition, using specific tasks and problem solving skills in order to reduce their symptoms.18 The components of a self-management program involve education, lifestyle modification and behavioural training.18 These components are listed in Table 11.

Studies have shown that the natural course of BPH is progressive.19-21 Therefore even patients who are good candidates for the initial selection of “watchful waiting” will require to be further evaluated in the future to determine if this strategy is still appropriate as their BPH progresses.

Table 10 lists predictors of higher risk of BPH progression.

Table 10 – Risk factors for BPH progression19,22

Older age Strong age related increase risk in treatment from: 3.3/1000 person-years for men 40-49 years old 30/1000 person-years for more than 70 years old or older

Baseline symptom score Men with moderate to severe symptoms (AUA-SI score greater than 7)Decreased peak urinary flow rate

Less than 12 ml. per second

Enlarged prostate Greater than 30 mLElevated PSA 1.4 ng./mL or greater

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Clinical Practice Tip:Acute urinary retention and invasive treatment occur in men using watching waiting but occur more frequently in men with large prostates and high PSA values

Serum PSA and prostate size can be used as parameters to advise men on their overall risk of complications but not as the sole basis for treatment recommendations.

Table 11 – Components of a BPH Self-Management Program18 Education and reassurance

Most patients want information about their condition and clinicians providing this information can help to reduce anxiety and treatment decision conflict

Addressing misconceptions or worries a patient has regarding their condition and its appropriate management is crucial

Informing patients of the lack of link between BPH and prostate cancer can have a dramatic impact on the patient’s anxiety associated with their symptoms

Lifestyle Modifications

Fluid Restriction o Has demonstrated efficacy in reducing incontinence in the elderlyo Recommend to reduce their excessive intake of fluid (>3 L of fluid per day) due to

the link between fluid intake and LUTS Caffeine and Alcohol

o Caffeine is both a diuretic and has bladder irritant effectso Patients with large consumption of caffeine have more LUTS and are more likely

to have a diagnosis of BPH and undergo BPH related surgeryo Alcohol consumption has been associated with urgency and higher AUA-SI scoreso Patients consuming large amounts of alcohol frequently are consuming a large

amount of fluid that contribute to LUTS Concurrent Medications

o Many medications may exacerbate LUTSo If possible alternatives may help to reduce LUTSo Diuretics – causes diuresiso Tricyclic antidepressants, antispasmodics and antihistamines may have

anticholinergic adverse effects and limit bladder emptyingo Antiparkinson drugs and calcium channel blockers cause smooth muscle

relaxation that may also reduce bladder emptyingBehavioural Training

Postvoid dribbleo Very common and bothersome for patientso By milking the urethra with a combination of leaning forward, perineal pressure

and contracting the pelvic floor muscles, urine that collects in the “u-bend” of the urethra after voiding can be expelled

Failure to empty bladder during urinationo This causes the bladder to prematurely fill and results in frequencyo Double voiding may help reduce the residual volume in the bladder. In this case

urine is passed twice in succession – the first void is performed normally in a relaxed and unhurried way, and then the second planned void is attempted within approximately 2 to 5 minutes.

Bladder Retrainingo May help to reduce LUTSo Patients resist the sensation of urinary urgency with distraction techniques and

pelvic floor squeezes to postpone voiding, thereby overcoming abnormal voiding patterns

o Initially, voiding should be postponed only for a short period of time (e.g. 1 minute). Once this is achieved with ease, patients can progress and postpone voiding for a longer time, aiming to increase their bladder capacity

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Case Challenge1. You start discussing different treatment options with Robert. You first discuss alpha blockers.

Which of the following alpha blocker is the MOST effective?a. Terazosinb. Doxazosinc. Tamsulosind. All of the above are equally effective

2. Which of the following is an advantage of using an alpha blocker in a patient like Robert?a. Decrease in prostate sizeb. Rapid onset of actionc. Decrease in the need for future BPH surgeryd. All of the above

Pharmacotherapy – Alpha Blockers

Current Recommendations: Alfuzosin, doxazosin, tamsulosin, and terazosin are appropriate and effective first line

treatment option for patients with bothersome, moderate to severe LUTS secondary to BPH (IPSS score ≥8).2

Although there are slight differences in the adverse events profiles of these agents, all four appear to have equal clinical effectiveness.2

Doxazosin and terazosin are reasonable choices but require dose titration and blood pressure monitoring.2

Second generation (doxazosin and terazosin) and third-generation (alfuzosin and tamsulosin) alpha blockers are a common treatment options for patients with LUTS associated with BPH.3 The alpha blocker prazosin is NOT recommended for BPH (Note: Current Australian guidelines recommend prazosin as first choice and it is the only subsidized alpha-blocker).23 The second and third generation alpha-blockers are well established as a treatment option for LUTS due to BPH.3

Mechanism of ActionTheir use is based on the hypothesis that BPH arises from bladder-outlet obstruction and a large proportion of cellular volume at the bladder neck and variable proportions of prostate volume is made up of smooth muscle, whose tension is mediated by alpha-adrenergic receptors.24 These agents inhibit the alpha1-adrenoreceptor and this causes a relaxing of the smooth muscle in the prostate and the bladder neck.3

EfficacyThis class of medication have a rapid onset of action, with typical improvements in symptom scores of 30-45% after 3 months of treatment.25 Although there are some slight differences in the side effects of the four medications, all of these agents are believed to be equally effective.3 At therapeutic doses

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these medications have comparable efficacy in lowering IPSS scores, increasing urine flow rates and improving symptoms.4

Alpha-blockers are effective at reducing symptoms but they unfortunately do not provide long-term reduction in the risk of acute urinary retention or BPH-related surgery.3 These medications do not shrink prostate volume or have any effect on PSA levels.

Adverse EffectsThe primary difference with the different alpha blockers are their side effect profiles.

Doxasozin and terazosin are not prostate selective and can have effect on the cardiovascular system of the patient. These two medications are more prone to causing postural hypotension and later rebound postural hypertension on withdrawal and require titrating or tapering over 2-3 weeks when being introduced or eliminated.4

Tamsulosin and alfuzosin are more selective in relaxing prostatic smooth muscle and have no effect on blood pressure.3 For this reason tamsulosin and alfuzosin do not need to be titrated and can be started directly at therapeutic dosage.3 Table 12 lists the most common side effects of the currently used alpha-blockers.

Table 12 – Adverse effects of currently used alpha blockers (placebo rates in parenthesis)24 Terazosin (%) Doxazosin (%) Alfuzosin (%) Tamsulosin (%)

Dizziness 3-26 (3-7) 17-24 (4-6) 2.1-7.4 (1.3-2.9) 3-11 (0-5)Hypotension 2-9 (0.5-1) 2.5-8.0 (0.0) 0.7-3.4 (0.0-3.4) 0.0 (0.5-1.0)Ejaculatory disorders 0.0-1.4 (0.0-1.0) 0.0 (0.0) 0.0-0.6 (0.0-1.3) 1.0-26.0 (0.0-1.0)Adapted from Reference 24

Pharmacotherapy – 5-Alpha Reductase Inhibitors (5-ARIs)

Current Recommendations: 5-ARIs may be used to prevent progression of LUTS secondary to BPH and to reduce the risk of

urinary retention and future prostate-related surgery.2

5-ARIs should not be used in men with LUTS secondary to BPH without prostatic enlargement. The 5-ARIs are appropriate and effective treatment alternatives for men with LUTS secondary

to BPH who have demonstrable prostate enlargement.2

5-alpha reductase inhibitors are commonly used in patients with BPH.23 These agents are an appropriate and effective treatment option for patients with LUTS associated with demonstrable prostatic enlargement (in patients without prostate cancer, PSA can be useful to estimate prostate size).23 This class of medication are the only hormonal therapy to date that demonstrates both efficacy and acceptable safety for the treatment of BPH.3

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Mechanism of Action5-alpha reductase inhibitors block the conversion of the main male androgenic steroid hormone testosterone to dihydrotestosterone (DHT).26 As was mentioned previously it is believed DHT is responsible for the increase in prostate cell growth associated with BPH. The two currently approved agents are finasteride and dutasteride.

Finasteride reduces plasma DHT levels by 60-70% and prostatic concentrations by approximately 85%.26 Dutasteride results in a 90-95% decrease in circulating DHT levels and prostatic concentrations by approximately 95%.26 This lowering of DHT levels leads to a decrease in prostate size.3

EfficacyFinasteride and dutasteride have been shown to decrease prostate volume (20-30%), lower IPSS scores by 3-4 points, increase in urine flow rates and decrease in urinary retention.10 Unlike alpha-blockers these agents have demonstrated a decrease in the need for BPH surgery by 48% and acute urinary retention by 57% compared to placebo.24

With the primary mechanism of action of these agents being atrophy in prostate tissue, they are most effective in patients with LUTS/BPH and demonstrable prostate enlargement.26 With prostate shrinkage being the key mechanism of action, it will normally take 3-6 months to see a significant reduction in symptoms.10 In a longer term study, 5-alpha reductase inhibitors decrease prostate volume by 30% and improve obstructive and irritative symptoms for at least 4 years 27

Adverse Effects5-alpha reductase inhibitors are generally well tolerated.25 Sexual side effects are the most common adverse effect reported, although there is a relatively high prevalence of sexual dysfunction in untreated men with BPH.25 Table 13 lists the most common adverse effects with this class of medication.

An important note for clinicians is that 5-alpha reductase inhibitors lead to a significant reduction in PSA levels. Fortunately this reduction is predictable and more importantly does not jeopardize the diagnostic performance of PSA for detecting prostate cancer.25 This class reduces PSA levels by approximately 50-60% after 6 months of treatment.25 Some data demonstrates PSA measurement on 5-alpha reductase inhibitors may have an enhanced sensitivity for detecting all prostate cancers as it eliminates the role of BPH on the PSA level.25 If a patient is experiencing an increase in PSA levels after the treatment nadir at 6-12 months after initiation of therapy of 5-alpha reductase inhibitor, adherence should be verified and if this has been confirmed they should be referred to an urologist to rule out prostate cancer.3

Table 13 – Adverse events of 5 alpha-reductase inhibitors (placebo rates in parenthesis)24 Finasteride(%) Dutasteride (%)

Ejaculatory disorders 4 (1) 2 (1)Erectile Dysfunction 8 (4) 7 (4)Decrease Libido 5 (3) 4 (3)Gynecomastia 1 (2) 2 (2)Notes: Bold values are significantly different from placebo (p<0.05) Adapted from reference 24

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Case ChallengeYou feel Robert is a good candidate for combination therapy of an alpha blocker and a 5-alpha reductase inhibitor.

1. Which one of the following statements is the MOST appropriate to use when discussing combination therapy?

a. Robert, combination therapy has rapid onset of action and can reduce the risk of your symptoms getting worse

b. Robert, people on combination therapy usually have less side effects than using either drug alone

c. Robert, combination therapy will reduce your symptoms but have little impact on your quality of life.

d. All of the above are appropriate to include2. If you were to start Robert on combination therapy with dutasteride and tamsulosin therapy. If

after 9 months he would like to discontinue one of his medications which would be the MOST appropriate to discontinue if he had improvement in his symptoms?

a. Dutasterideb. Tamsulosinc. Neither once started as combination therapy they must be continued togetherd. Both as the prostate size is smaller and does not need therapy

Pharmacotherapy – Combination Therapy

Current Recommendation: The combination of an alpha-blocker and a 5-ARIs (combination therapy) is an appropriate

and effective treatment for patients with LUTS associated with demonstrable prostatic enlargement based on volume measurement, PSA level as a proxy for volume, and/or enlargement on DRE.2

With the key differences between the alpha blockers and 5-alpha reductase inhibitors in terms of efficacy and onset of action there was interest in combination therapy. Alpha blockers offer rapid symptom relief without targeting the underlying disease process while 5-alpha reductase inhibitors provide mid and long-term symptom relief as well as a reduction in the risk of progression of BPH such as acute urinary retention and BPH-related surgery.25 Current guidelines recommend the combination therapy in patients with moderate to severe symptoms associated with prostate enlargement.23

Two trials evaluated the combination of an alpha-blocker and 5-alpha reductase inhibitor to treat patients with BPH. The first trial was the MTOPS study.21 This trial compared the combination of finasteride and doxazosin and compared it to either of the agents alone. The second trial was the CombAT study.28 This trial evaluated the combination of dutasteride and tamsulosin and compared it to either agent individually. Both trials demonstrated combination therapy was superior for symptom

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control and both caused a decrease in prostate volume. The key points regarding each study are listed in Table 14.

Combination therapy was not only highly effective in reducing symptoms but improved a patient’s quality of life.29 One study demonstrated the combination of dutasteride and tamsulosin resulted in a greater patient reported quality of life and treatment satisfaction than both monotherapy with either agent alone at 2 years.30

Table 14 – Key Points regarding CombAT and MTOPS StudyCombAT29 MTOPS21

Study Design 4844 men Average IPSS score 16.4 Prostate volume > 30 mL (mean 55 mL) Qmax between 5mL/s and 15 mL/s Post-void residual volume 68 mL (mean)

Patients randomized to receive: Dutasteride Tamsulosin Dutasteride and tamsulosin

Findings at 4 year follow-up The combination regimen was associated with:

o A significantly greater reduction in risk of clinical progression,* compared tamsulosin and dutasteride monotherapy

o Significantly greater symptom benefit, at 3 months for dutasteride monotherapy and at 9 months with tamsulosin monotherapy

o A significantly greater reduction in risk of primary endpoint events (i.e. acute urinary retention or BPH-related surgery) when compared with tamsulosin monotherapy, but not when compared with dutasteride; p = 0.18)

The combination regimen was generally well tolerated

The benefits on prostate volume and Qmax with combination and dutasteride monotherapy at 24 months was significantly greater than tamsulosin monotherapy and maintained to month 48

Study Design 3047 men with BPH Average IPSS score 16.9 Prostate volume 36.3±20.1 mL Qmax = 10.5 (mean) Post-void residual volume 68.1 mL (mean)

Patients randomized to receive: Finasteride Doxazosin Finasteride and doxazosin Placebo

Findings at 4.5 year follow-up The combination regimen was associated with:

o A significantly greater reduction in risk of clinical progression (primary endpoint),* compared with finasteride monotherapy, doxazosin monotherapy or placebo

o Significantly greater symptom benefit, compared with either finasteride or doxazosin monotherapy

o A significantly greater reduction in risk of acute urinary retention or BPH-related surgery, compared with placebo (finasteride monotherapy was also associated with a significant risk reduction in this regard, but doxazosin monotherapy was not)

o The benefit of combination therapy – in terms of its effect on symptoms and risk of long-term progression – was most apparent among patients who had larger prostates at baseline (i.e. ≥ 25 mL)

The combination regimen was generally well tolerated

Clinical progression = Any of the following: ≥ 4-point deterioration in symptom score (confirmed); acute urinary retention; urinary incontinence; recurrent urinary tract infection or urosepsis; renal insufficiency.

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Adverse Effects of Combination TherapyOverall a similar proportion of adverse effects were reported in each treatment group in the combination therapy trials.9 These adverse effects were similar to those of each drug alone versus placebo.10 The most common adverse effects with combination therapy were erectile dysfunction, ejaculatory disorders and decreased libido.25

Combination Therapy Long-TermThe 4 year results of the CombAT and MTOPS studies provide some insight in the use of combination therapy of 5-alpha reductase inhibitors and alpha blockers long-term. The following are some key points of these trials: 29 21

In patients with moderate to severe LUTS due to BPH, alpha-blocker and 5 alpha reductase combination therapy reduced the relative risk of clinical progression of BPH compared to either therapy alone or placebo

There was no significant difference in acute urination retention and BPH related surgery between the combination therapy and 5 alpha reductase inhibitor monotherapy.

The effectiveness of alpha-blocker monotherapy decreased over time and this is likely due to the significant increase in prostate volume compared to both the combination and 5 alpha-reductase inhibitor monotherapy group

Long-term adverse effects of combination therapy were similar to each drug alone compared to placebo.

From Combination Therapy to Monotherapy

Discontinuing the Alpha-Blocker in the Combination TherapyBoth the SMART trial 31 and the PROACT trial32 indicate for many patients the alpha blocker in the combination therapy regimen can be safely discontinued after 6-9 months of combination therapy with no decrease in perceptible efficacy. The potential advantages of discontinuing the alpha-blocker include lower cost, fewer adverse effects and better adherence. The results of the CombAT and MTOPS trials question this result as long-term combination therapy with alpha blockers and 5-alpha reductase inhibitors demonstrated a reduced risk of BPH symptom progression than either agent alone.33,34

Some guidelines advise clinicians to give patients on combination therapy the option to discontinue the alpha blocker after 6-12 months. If symptoms recur, the alpha blocker should be restarted.

Discontinuing the 5-Alpha Reductase Inhibitor in the Combination TherapyOne study evaluated the discontinuation of the 5-alpha reductase inhibitor in patients receiving 1 year combination therapy.35 After the 1 year of the combination therapy patients demonstrated a 24.5-26.1% reduction in prostate volume. At this point the 5-alpha reductase inhibitor was discontinued for 1 year and the average patients saw an 18.6-20.7% increase in prostate volume and a significant deterioration in their IPSS score. For this reason the author concluded that lifelong use of 5-alpha reductase inhibitors should be considered to prevent BPH progression.35

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Complementary and Alternative Medicines (CAM)

Current Recommendations: No dietary supplement, combination phytotherapeutic agent or other nonconventional

therapy is recommended for the management of LUTS secondary to BPH.2

At this time, the available data do not suggest that saw palmetto has a clinically meaningful effect on LUTS secondary to BPH.2

Phytochemicals are plant derived non-nutritive compounds with protective or disease preventing properties.3 This class of agents have been the subject of increasing interest in the treatment of BPH. These medications have very little adverse effects and a low risk of drug interactions.10

In some studies the use of the phytochemical saw palmetto has demonstrated mild to moderate efficacy in reducing nocturia, increasing maximal urinal flow and improving scores in men with BPH with results comparable to tamsolusin.3 Other trials have not demonstrated any beneficial effects compared to placebo.3 A Cochrane Collaboration review of the published studies concluded saw palmetto to be no more effective than placebo for the treatment of LUTS associated with BPH.36

Anticholinergic Agents

Current Recommendations: Anticholinergic agents are appropriate and effective treatment alternatives for the

management of LUTS secondary to BPH in men without an elevated post-void residual and when LUTS are predominantly irritative.2

Combination therapy with an alpha receptor antagonist and anticholinergic can be helpful for selected patients with bladder outlet obstruction due to BPH and concomitant detrusor overactivity.12

Prior to initiation of anticholinergic therapy, baseline PVR urine should be assessed. Anticholinergics should be used with caution in patients with a post-void residual greater than 250 to 300 mL.2

Overactive bladder (OAB) is a syndrome of storage LUTS, defined as urgency with or without urgency incontinence, usually with increased daytime frequency and nocturia and is commonly attributed to detrusor overactivity.37 Approximately 11% to 16% of men in Europe and North America have OAB symptoms, and many men with benign prostatic obstruction (BPO) have concomitant detrusor overactivity.37 Evidence suggests that OAB symptoms may occur either secondarily to or independently from BPO in men.37

Mechanism of ActionAnticholinergic agents interrupt the interaction between acetylcholine and cholinergic (muscarinic) receptors.2 Blockade of this interaction results in a reduction in smooth muscle tone and theoretically an amelioration of diseases associated with excess contraction of these muscles.2

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EfficacyA recent systematic review of the use of anticholinergics in patients with storage LUTS concluded anticholinergics, alone or in combination with alpha-blockers appear to be an effective and safe treatment of storage symptoms suggestive of OAB.37 The authors of this review suggest:37

Use of anticholinergic alone:o Men with storage LUTS with no significant history of voiding LUTSo AVOID in men with significant bladder outlet obstruction, a history of acute urinary

retention, high serum PSA levels, high post void residual, or low flow rate Use of anticholinergic in combination with alpha blocker

o Men with bladder outlet obstruction and overactive bladder symptoms resulting from concomitant or secondary bladder condition who have not responded to treatment with alpha blockers or 5-alpha reductase inhibitors alone.

o AVOID in men with storage LUTS with no significant history of voiding LUTS or men with clinically significant bladder outlet obstruction.

Adverse EffectsThe most common anticholinergic agent used in clinical trials is tolterodine.2 Dry mouth is the most common adverse effect reported, occurring between 20-25% of patients.2 Other common adverse effects of anticholinergic therapy include drowsiness and constipation (such side effects are less commonly associated with newer anticholinergic agents, compared with older members of the class).

SurgerySurgical treatment of BPH is necessary if medical treatments fail, or if benign prostatic obstruction causes renal insufficiency, urinary retention, recurrent urinary tract infections, bladder calculi or hydronephrosis 3

Transurethral resection of the prostate (TURP) is the standard for surgical treatment of BPH with up to 77% improvement in symptoms and 100% improvement in urinary flow.38 Transurethral incision of the prostate (TUIP) is the procedure of choice for smaller prostates. Laser prostatectomy shows high levels of symptomatic improvement 56% to 68% and 56% to 100% improvement in urinary flow. 38

Surgeries are associated with postoperative risks such as erectile dysfunction (4% to 10% incidence) and urinary incontinence (0.5% to 1.5%). The 5-year recurrence rate of BPH following surgery is 2% to 10%.4

Minimally-invasive surgery for BPH does not appear to have better outcomes than traditional surgery. There are lower levels of symptomatic improvement and flow improvement and higher rates of reoperation.39

Follow up and Shared-CareBPH tends to be a progressive condition with a change in symptoms over time. For this reason primary care physicians are encouraged to monitor these patients at least annually with a digital rectal exam and a PSA test.

25

When initiating or changing BPH therapy, consider evaluating the patient at least every 6 months. A quick checklist to use during reassessment appointment includes:

Individual symptom improvements or regression (consider use of IPSS) Changes in symptoms (void LUTS versus storage LUTS) Adherence to lifestyle modifications The patient’s level of adherence to therapy Any possible side effects of therapy and the severity of these adverse effects The patient’s overall satisfaction with therapy Whether the patient’s overall BPH management strategy – including his prescribed

pharmacotherapy – needs to be changed or adjusted.

With the increasing incidence of BPH there is a call for more shared care between urologist and primary care physicians. Primary care physicians are ideally positioned to case detect, assess and when appropriate initiate BPH treatment. When patients present with more complicated symptoms or conditions (see table 9) patients should be referred to urologists for further assessment, treatment changes or a surgical procedure. Once the urologist has evaluated and when appropriate modified the treatment regimen, the care of the patient will commonly passed back to the primary care physician for ongoing monitoring. In this shared-care model the expertise of both the urologist and family physician are maximized and can lead to better delivery of care to patients with BPH.40

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Summary of the Medical Therapies for Benign Prostatic HyperplasiaCurrent Medical Therapies for the treatment of BPH10,23

Type of Therapy & Agents

Mechanism of action

Side effects Normal Dosages Clinical Notes

Alpha-adrenergic agents(tamsulosin, alfuzosin, terazosin, doxazosin)

Decrease prostatic and urethral smooth muscle tone

Hypotension, headache, dizziness, ejaculation disorders, rhinitis

Alfuzosin:10 mg dailyTamsulosin0.4-0.8 mg dailyTerazosininitiate at 1 mg at bedtime for 1 week increase at weekly intervals until maintenance dose of 5, 10 mg at bedtimeDoxazosininitiate at 1 mg at bedtime for 1 week and increase weekly until 4-8 mg daily

All agents are thought to be equally effective

Rapid onset of action All lower IPSS scores, increase urine

flow rates and improve LUTS Do NOT reduce the risk of BPH related

surgery or acute urinary retention Titration and tapering is required for

doxazosin and terazosin Prostate specific agents of alfuzosin

and tamsulosin have a higher incidence of sexual side effects but low risk of cardiovascular adverse effects

5-Alpha Reductase inhibitors(Dutasteride, finasteride)

Block the conversion of testosterone to dihydro-testosterone

Decreased libido, erectile dysfunction, ejaculation disorders

Dutasteride:0.5 mg dailyFinasteride 5 mg daily

Reduce prostate volume and reduce symptoms

Reduces the risk of acute urinary retention and BPH surgery

Efficacy is maintained over the long-term

Onset of action is 3 to 6 months Generally well tolerated. Sexual side

effects are the most common adverse effects

Decreases PSA levels by 50%

Combination therapy:Alpha blocker and 5-alpha reductase inhibitor

Side effects similar to those of each drug alone

Superior to monotherapy in reduction of symptoms

More successful than either agent alone in preventing clinical progression

If patient wishes the alpha-blocker can be discontinued after 6-9 months

Anticholinergics(tolterodine)

Block interaction of acetylcholine at the muscarinic receptors and reduces smooth muscle tone

Dry mouth, drowsiness and constipationThere is a slight increased risk of urinary retention

Tolterodine2 mg or 4 mg daily

Can help in patients with concomitant overactive bladder and BPH

Consider in patients with significant storage LUTS and low voiding LUTS

Caution in patients at risk of acute urinary retention and with significant post-void residual volume

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Key Learning Points1. BPH is a highly prevalent condition that affects the majority of men as they age2. BPH is the leading cause of lower urinary tract symptoms (LUTS) in older men3. Many patients with BPH do not discuss their symptoms with their physician even though there

are highly effective treatment strategies available4. The IPSS is a quick and effective method to score the severity of BPH symptoms but also the

bother of these symptoms and their impact on a patient’s quality of life5. PSA level can be used as a surrogate marker of prostate volume in absence of cancer6. Treatment goals for BPH include:

a. Improve symptoms, improve urinary flow and decrease impact on quality of life and activities

b. Reduce progression of BPH and reduce the risk of acute urinary retention and the need for BPH related surgery

7. Current guidelines provide treatment recommendations based on:a. Symptom severityb. Prostate sizec. How much the symptoms bother the patient

8. Alpha Blockers are a treatment option for most patients. Key points on alpha-blockers include:a. Relax smooth muscle in the prostate and bladder neckb. Rapid onset of action and improve symptom scores by 30-45% in 3 monthsc. Do NOT provide long-term reduction in the risk of surgeryd. Each alpha-blocker has similar efficacy but differ based on their adverse effectse. Older medications (terazosin, doxazosin) have a higher incidence of dizziness and

hypotension and have to be titrated slowly to the therapeutic dose over several weeksf. Newer medications (alfusozin, tamsulosin) are more prostate selective with less

cardiovascular side effects but a higher risk of sexual adverse effects9. 5-alpha reductase inhibitors are a treatment option for patients. Key points on 5-alpha

reductase inhibitors include:a. Reduce the conversion of testosterone to DHT and thereby reduce prostate volumeb. Slow onset of action (3-6 months)c. Effective at reducing symptoms and maintain this efficacy over the long-termd. Reduce progression of symptoms and risk of acute urinary retention and need for BPH

related surgerye. Are associated with some sexual side effects

10. Combination therapy is commonly used for patients with BPH. Some of the key points on combination therapy include:

a. Best of both key classes with a rapid onset of action and maintaining efficacy over the long-term

b. Adverse effects are similar to those of each drug alone

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11. Complementary medical therapy (e.g. saw palmetto) is not a recommended treatment option for patients with BPH, but appears to be safe

12. Surgery is necessary if medical treatments fail or if the patient is starting to experience complications associated with BPH

29

References1. Sexton CC, Coyne KS, Kopp ZS, et al. The overlap of storage, voiding and postmicturition symptoms and implications for treatment seeking in the USA, UK and Sweden: EpiLUTS. BJU Int. 2009;103 Suppl 3:12-23. Available at: Accessed February 16, 2011.

2. McVary K, Roehrborn CG, Avins A, et al. American Urological Association Guideline: Management of Benign Prostatic Hyperplasia (BPH). American Urological Association; 2010. Available at: http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines.cfm?sub=bph. Accessed February 15, 2011.

3. Tanguay S, Awde M, Brock G, et al. Diagnosis and management of benign prostatic hyperplasia in primary care. Can Urol Assoc J. 2009;3(3 Suppl 2):S92-S100. Available at: .

4. Levy A, Samraj GP. Benign prostatic hyperplasia: when to “watch and wait,” when and how to treat. Cleveland Clinic Journal of Medicine. 2007;74(Suppl_3):S15-S15. Available at: Accessed February 12, 2010.

5. Platz E, Kawachi I, Rimm E, Willett W, Giovannucci E. Race, Ethnicity and Benign prostatic hyperplasia in the Health Professionals Follow-Up Study. The Journal of Urology. 2000;163(2):490-495. Available at: Accessed February 13, 2010.

6. Fowke JH, Murff HJ, Signorello LB, Lund L, Blot WJ. Race and Socioeconomic Status are Independently Associated with Benign Prostatic Hyperplasia (BPH). J Urol. 2008;180(5):2091-2096. Available at: .

7. Nandeesha H. Benign prostatic hyperplasia: dietary and metabolic risk factors. Int Urol Nephrol. 2008;40(3):649-656. Available at: Accessed February 17, 2011.

8. Nickel JC, Downey J, Bénard F, et al. The Canadian Benign Prostatic Hyperplasia Audit Study (CanBas). Can Urol Assoc J. 2008;2(4):367-373. Available at: .

9. Emberton M, Fitzpatrick JM, Garcia-Losa M, Qizilbash N, Djavan B. Progression of benign prostatic hyperplasia: systematic review of the placebo arms of clinical trials. BJU International. 2008;102(8):981-986. Available at: Accessed February 13, 2010.

10. Davidson JH, Chutka DS. Benign prostatic hyperplasia: treat or wait? J Fam Pract. 2008;57(7):454-463. Available at: Accessed February 12, 2010.

11. Wolters R, Wensing M, Weel CV, Wilt GJVD, Grol RPTM. Lower urinary tract symptoms: social influence is more important than symptoms in seeking medical care. BJU International. 2002;90(7):655-661. Available at: Accessed February 12, 2010.

12. Nickel JC, Menez-Probst C, Whelan T, Paterson R, Razvi H. 2010 Update: Guidelines for the management of benign prostatic hyperplasia. Canadian Urological Association Journal. 2011;4(5):310-316. Available at: .

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13. Abrams P, Chapple C, Khoury S, Roehrborn C, de la Rosette J. Evaluation and Treatment of Lower Urinary Tract Symptoms in Older Men. The Journal of Urology. 2009;181(4):1779-1787. Available at: Accessed February 17, 2011.

14. Andrology Austrlia. Prostate disease: BPH and Prostatitis - Diagnosis and management. Available at: http://www.andrologyaustralia.org/dbClinicalGuidelines.asp?pageCode=CLINICALGUIDELINES. Accessed February 18, 2011.

15. Roehrborn CG, McConnell J, Bonilla J, et al. Serum prostate specific antigen is a strong predictor of future prostate growth in men with benign prostatic hyperplasia. PROSCAR long-term efficacy and safety study. J. Urol. 2000;163(1):13-20. Available at: Accessed February 14, 2010.

16. Roehrborn CG, McConnell JD, Lieber M, et al. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. PLESS Study Group. Urology. 1999;53(3):473-480. Available at: Accessed February 14, 2010.

17. Bartsch G, Fitzpatrick JM, Schalken JA, et al. Consensus statement: the role of prostate-specific antigen in managing the patient with benign prostatic hyperplasia. BJU International. 2004;93(s1):27-29. Available at: Accessed February 14, 2010.

18. Brown C, Emberton M. Self-management for men with lower urinary tract symptoms. Current Urology Reports. 2009;10(4):261-266. Available at: Accessed February 12, 2010.

19. Jacobsen SJ, Jacobson DJ, Girman CJ, et al. Treatment for benign prostatic hyperplasia among community dwelling men: the Olmsted County study of urinary symptoms and health status. J. Urol. 1999;162(4):1301-1306. Available at: Accessed February 14, 2010.

20. Roehrborn CG. Alfuzosin 10 mg once daily prevents overall clinical progression of benign prostatic hyperplasia but not acute urinary retention: results of a 2-year placebo-controlled study. BJU Int. 2006;97(4):734-741. Available at: Accessed February 14, 2010.

21. McConnell JD, Roehrborn CG, Bautista OM, et al., the Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The Long-Term Effect of Doxazosin, Finasteride, and Combination Therapy on the Clinical Progression of Benign Prostatic Hyperplasia. N Engl J Med. 2003;349(25):2387-2398. Available at: Accessed February 14, 2010.

22. Wiygul J, Babayan RK. Watchful waiting in benign prostatic hyperplasia. Current Opinion in Urology. 2009;19(1):3-6. Available at: Accessed February 24, 2011.

23. Nickel JC, Herschorn S, Corcos J, et al. Canadian guidelines for the management of benign prostatic hyperplasia. Can J Urol. 2005;12(3):2677-2683. Available at: Accessed February 13, 2010.

24. Sandhu JS. Therapeutic options in the treatment of benign prostatic hyperplasia. Patient Prefer Adherence. 3:213-223. Available at: .

25. Emberton M, Cornel EB, Bassi PF, et al. Benign prostatic hyperplasia as a progressive disease: a guide to the risk factors and options for medical management. Int J Clinical Practice. 2008;62(7):1076-1086. Available at: Accessed February 12, 2010.

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26. Laborde EE, McVary KT. Medical Management of Lower Urinary Tract Symptoms. Rev Urol. 2009;11(Suppl 1):S19-S25. Available at: .

27. Roehrborn CG, Lukkarinen O, Mark S, et al. Long-term sustained improvement in symptoms of benign prostatic hyperplasia with the dual 5alpha-reductase inhibitor dutasteride: results of 4-year studies. BJU Int. 2005;96(4):572-577. Available at: Accessed February 14, 2010.

28. Roehrborn CG, Barkin J, Siami P, et al. Clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (BPH) by baseline characteristics: 4-year results from the randomized, double-blind Combination of Avodart and Tamsulo. BJU International. 2011:no-no. Available at: Accessed February 19, 2011.

29. Roehrborn CG, Siami P, Barkin J, et al. The Effects of Combination Therapy with Dutasteride and Tamsulosin on Clinical Outcomes in Men with Symptomatic Benign Prostatic Hyperplasia: 4-Year Results from the CombAT Study. European Urology. 2010;57(1):123-131. Available at: Accessed February 19, 2011.

30. Barkin J, Roehrborn CG, Siami P, et al. Effect of dutasteride, tamsulosin and the combination on patient-reported quality of life and treatment satisfaction in men with moderate-to-severe benign prostatic hyperplasia: 2-year data from the CombAT trial. BJU Int. 2009;103(7):919-926. Available at: Accessed February 14, 2010.

31. Barkin J, Guimarães M, Jacobi G, et al. Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride. Eur. Urol. 2003;44(4):461-466. Available at: Accessed February 14, 2010.

32. Nickel JC, Barkin J, Koch C, Dupont C, Elhilali M. Finasteride monotherapy maintains stable lower urinary tract symptoms in men with benign prostatic hyperplasia following cessation of alpha blockers. Can Urol Assoc J. 2008;2(1):16-21. Available at: .

33. Roehrborn CG, Siami P, Barkin J, et al. The Effects of Combination Therapy with Dutasteride and Tamsulosin on Clinical Outcomes in Men with Symptomatic Benign Prostatic Hyperplasia: 4-Year Results from the CombAT Study. European Urology. 2010;57(1):123-131. Available at: Accessed February 14, 2010.

34. McConnell JD, Roehrborn CG, Bautista OM, et al. The Long-Term Effect of Doxazosin, Finasteride, and Combination Therapy on the Clinical Progression of Benign Prostatic Hyperplasia. New England Journal of Medicine. 2003;349(25):2387-2398. Available at: .

35. Jeong YB, Kwon KS, Kim SD, Kim HJ. Effect of discontinuation of 5alpha-reductase inhibitors on prostate volume and symptoms in men with BPH: a prospective study. Urology. 2009;73(4):802-806. Available at: Accessed February 14, 2010.

36. Tacklind J, MacDonald R, Rutks I, Wilt TJ. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2009;(2):CD001423. Available at: Accessed February 14, 2010.

37. Kaplan SA, Roehrborn CG, Abrams P, et al. Antimuscarinics for treatment of storage lower urinary tract symptoms in men: a systematic review. International Journal of Clinical Practice. 2011:no-no. Available at: Accessed February 19, 2011.

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38. Hoffman RM, MacDonald R, Wilt TJ. Laser prostatectomy for benign prostatic obstruction. Cochrane Database Syst Rev. 2004;(1):CD001987. Available at: Accessed February 15, 2010.

39. Lourenco T, Pickard R, Vale L, et al. Minimally invasive treatments for benign prostatic enlargement: systematic review of randomised controlled trials. BMJ. 2008;337:a1662. Available at: Accessed February 15, 2010.

40. Nickel JC. Do more BPH patients mean more urologists or just better management strategies? Can Urol Assoc J. 2010;4(2):127-128. Available at: Accessed 16:15:27.

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