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PRIORITY PRESS - Primary Care Today 2013

Toronto, Ontario / May 9-11, 2013

Toronto - Lower urinary tract symptoms (LUTS) in older males are a common clinical problem and are often secondary to the development of benign prostatic hyperplasia (BPH). Treatment goals include a reduction in daytime frequency, hesitancy and nocturia and an increase in stream as well as complete emptying. Two main drug classes are indicated in the management of BPH. The a-blockers can rapidly ameliorate voiding symptoms while the 5a-reductase inhibitors (5ARIs) alter the natural history of the disease over time. In select patients, the combination of the two may be more effective in men with more severe symptoms, higher prostatic specific antigen (PSA) levels and bigger prostates. The use of a long-acting PDE5 inhibitor may also be appropriate for the treatment of LUTS in men who are experiencing erectile dysfunction (ED).

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Here at Primary Care Today, several sessions were dedicated to BPH—why it happens, how it presents, and what to do about it when BPH is uncomplicated or complicated by a high PSA level or by ED. “As men get older, prostates get bigger and men develop urinary problems,” Dr. Arun Mathur, urologic oncologist, Durham Regional Cancer Centre, Oshawa, Ontario, told delegates here.

The enlarged prostate then tends to squeeze or partly block the urethra, Because the bladder has to push harder against the smaller urethral opening on urination, the bladder becomes thick-walled and dysfunctional, inappropriately contracting with no warning and resulting in a sudden urge to urinate. Since the bladder can only contract for 2 to 3 minutes at a time, only part of the urine in the bladder is emptied on each voiding, resulting in frequency of urination both during the day and at night.

The pathology of inappropriate contractions, reduced blood flow and reduced nerve function also describes much of what happens to produce erectile dysfunction (ED), as Dr. Mathur pointed out. Because the PDE5 inhibitors affect both the bladder and the prostate, “all PDE5 inhibitors have been shown to improve BPH so these drugs do help men urinate and all help improve urination equally,” Dr. Mathur said.

This is a convenient coincidence, he added, as men who have both BPH and ED, a not uncommon comorbid condition, may be rationally treated with the long-acting PDE5 inhibitor, tadalafil, at a dose of 5 mg a day.

At that dose, tadalafil has been shown to be as effective as the alpha-blocker tamsulosin in men with BPH, as Dr. Mathur indicated.

Diagnostic Considerations

According to the most recent Canadian Urological Association guidelines (Can Urol Assoc J 2010;4(5):310-16), physicians need to take a careful history from a typical male presenting with LUTS. Symptoms secondary to BPH include frequency, urgency, nocturia, poor flow, incomplete emptying, hesitancy and straining to void. “Physicians also need to do a focused physical exam including examination of the abdomen and external genitalia,” Dr. Paul Whelan, Professor of Urology, McMaster University, Hamilton, noted. A digital rectal exam (DRE) should also be part of the routine physical exam. The CUA also recommends physicians do a urine analysis. A PSA level is not mandatory but can be a useful surrogate marker of prostate size. PSA levels also predict the risk of BPH progression as well as progression to urinary retention and subsequent surgery. Findings on the DRE and the PSA level should also correlate.

For example, a 51-year old male with a PSA of 3.5 ng/mL and a tiny prostate, “is worrisome,” Dr. Whelan explained, “as it suggests prostate cancer may be present.” However, an 85-year old male with a PSA of 6.0 ng/mL and a prostate the size of a grapefruit, “you can be less concerned [about] prostate cancer.” It is important to take age-adjusted PSA levels into consideration in the context BPH diagnosis, as a PSA of 4.0 ng/mL, for example, in a patient 40 to 49 years of age is abnormal.

Treatment Selection

Selecting the appropriate agent for the treatment of BPH depends on symptom severity, the degree of bother symptoms, prostate size and the side effects of the agent(s) used to treat BPH. It also depend on whether or not ED is present, which shares certain features of BPH pathophysiology including altered smooth muscle contraction and reduced blood flow. If symptoms are not bothering the patient, nothing needs to be done although if the patient has a large prostate, the CUA notes that a 5ARI may be considered in these patients.

For  LUTS secondary to BPH, both the a-blockers and the 5ARIs may be considered. The a-blockers relax contraction of smooth muscle in the bladder neck and the prostatic urethra by blocking a₁-adrenoreceptors and have a rapid onset of action but do not alter the natural history of the disease. The 5ARIs decrease conversion of testosterone to dihyrotestosterone, reducing prostate volume and may take about 6 months before they begin to affect prostate size. By shrinking prostate volume, they do alter the natural history of the disease.

Improvement in symptom control has been demonstrated for all a-blockers. However, terazosin and doxazosin are non-selective—“basically they were anti-hypertensive drugs that weren’t very good antihypertensives and they got to have a second life being BPH drugs,” Dr. Whelan remarked.

Rationale for  High a₁ Selectivity

Selective a-blockers were specifically designed to treat BPH and include tamsulosin, alfuzosin and silodosin. “What we are looking for here is to affect the a_1a receptor,” Dr. Whelan explained. The a_1a receptors are highly concentrated in the prostate, bladder base and prostatic urethra; they probably have some impact on the bladder wall as well.

Among the a-blockers, the most selective is silodosin, which is highly selective for the a_1a receptor, at a a_1a: a_1b ratio of 162:1 compared to a 10:1 and 1:1 ratio for tamsulosin and alfuzosin, respectively.

In the silodosin pivotal North American trial (J Urol 2009;181:2634-40), mean change in total IPSS (International Prostate Symptom Score) from baseline was -3.5 at 12 weeks compared to -6.4 for placebo (P<0.001). Mean peak urine flow rate increased 2.8 mL/sec within 2 to 6 hours of the first dose of silodosin. “The impact is basically within the first day,” Dr. Whelan observed. “So if you had a patient with impending urinary retention and you started them on this agent, within a day they would markedly improve, so there is an advantage to using silodosin in that situation, it has a very rapid onset of action.”

According to Dr. Whelan, a-blocker use in elderly patients “is a significant issue,” because it can cause postural hypotension and patients may fall down and break their hip. Other side effects most common with the non-selective a-blockers can be quite debilitating and include dizziness, headache and nausea as Dr. Whelan noted—“reason[s] why I don’t like to use the non-selective agents.” Men may also complain about retrograde ejaculation. “Once you explain what is happening to them physiologically, it usually resolves the issue.” Dr. Whelan concluded that selective a-blockers offer excellent overall symptom control and are generally very well tolerated.

Combination Therapy

Once BPH progresses and the a-blocker is no longer working or if patients have moderate to severe LUTS, a PSA >1.4 ng/Ml and a prostate >30 cc in size, “then combination therapy may be the right thing for that patient,” Dr. Whelan noted. The MTOPS and CombAT trials evaluated the impact of using an a-blocker/5ARI combination on the incidence of BPH progression and both trials showed significantly less BPH progression in the combination arms. On initiation of a 5ARI ±a-blocker, Dr. Whelan cautioned that clinicians should expect to see a 50% drop in the patient’s PSA level some 6 months later after which it essentially “flat-lines” from there on.

If clinicians do observe fluctuations in the PSA after it’s been low and stable—even with increases of 0.5 to 1.0 ng/mL —“this is highly predictive of prostate cancer and patients should see a urologist,” Dr. Whelan warned. The 5ARIs have a clear benefit in that finasteride and dutasteride have been shown to reduce the risk of prostate cancer by 25% over 4 years. If men develop prostate cancer on a 5ARI, they appear to be more likely to develop a high-grade prostate cancer— a reason the FDA added new safety information on 5ARI labels in 2011.

Patients also need to be counselled about the 5ARIs side effects. “When you talk to patients about being on a 5ARI, they definitely have decreased libido,” Dr. Whelan noted. They may also inhibit orgasm and patients can develop ED.

On 5ARI therapy, there is also about a 3% risk of developing gynecomastia and “it is not reversible,” Dr. Whelan emphasized. “And the only treatment is cosmetic mastectomy which is a painful operation in an older man. So you need to stress that if patients start to develop breasts, they need to get off the medication.”

Summary

BPH is common among older males but remains amenable to several different therapeutic approaches. Patient selection is key as variables including the size of the prostate help shape treatment selection as does the presence of ED. If medical therapy proves unsatisfactory, new surgical techniques including the use of specific laser therapy should help resolve symptomatic complaints.