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Management of benign prostatic hyperplasia (BPH)

Posted by admin on June 3rd, 2010 No Comments

The National Prescribing Centre (NPC) [UK]

Summary

Symptoms of benign prostatic hyperplasia (BPH) are common in older men. They result from hyperplasia of glandular tissue and increased smooth muscle tone. Many men accept these symptoms as a normal part of the ageing process, and do not seek treatment.

As BPH is not always a progressive condition, and the incidence of complications is low, ‘watchful waiting’ is appropriate for men whose symptoms are mild.

Men suffering severe symptoms, or who develop complications of benign prostatic hyperplasia such as acute urinary retention or recurrent urinary tract infection, should be referred to a urologist for consideration of surgical treatment.

Transurethral resection of the prostate is the most commonly used surgical procedure. It is more effective than drug therapy, but is occasionally associated with complications such as impotence and incontinence.

Alphaj-adrenoceptor blocking drugs reduce smooth muscle tone in the prostatic tissue and bladder neck, decreasing resistance to urinary flow. They can produce cardiovascular side-effects, such as hypotension.

Tamsulosin (Flomax MR, capsules, 400 micrograms) is an inhibitor of the α1A-receptor subtype, which is thought to be predominant in the prostate. No convincing evidence exists that this results in fewer adverse effects compared to other α1-blockers.

Finasteride (Proscar, tablets, 5mg) inhibits 5α-reductase, resulting in shrinkage of prostatic glandular tissue. There is evidence that finasteride also reduces the risk of acute urinary retention and need for surgery, although such events are relatively uncommon.

Patients should be informed of the advantages and disadvantages of all treatment options, and should participate in the choice of therapy.

What is benign prostatic hyperplasia?

BPH is a benign enlargement of the prostate gland which occurs as a consequence of ageing. This leads to narrowing of the urethra, which may result in difficulty in passing urine. Prostatic enlargement is believed to be the result of two processes:

• hyperplasia of glandular tissue, under the stimulus of dihydrotestosterone (DHT); and

• increased smooth muscle tone, both within the prostate and in the bladder neck, under the control of α1-adrenoceptors.

Medical treatment of benign prostatic hyperplasia aims to alter these processes, either by inhibiting 5α-reductase, the enzyme responsible for the formation of DHT, or by blockade of α1-adrenoceptors.

Patients suffering from BPH may present with a variety of the following symptoms, which may be classified as:

• ‘filling’ symptoms: such as frequency, urgency, and nocturia; or

• ‘voiding’ symptoms: e.g. poor urinary stream, intermittent stream, hesitancy and terminal dribbling.

Symptoms from either or both categories may occur. While they may be irritating, these symptoms do not in themselves have serious consequences. However, on some occasions, bladder outflow obstruction resulting from benign prostatic hyperplasia may lead to recurrent urinary tract infection (UTI) and pyelonephritis, or chronic urinary retention and hydronephrosis.

How common is it?

Symptoms of BPH may be found in a large number of men over the age of 60, and the prevalence rises with age. There is a lack of consensus on an exact definition for the condition; differences in criteria for the diagnosis of benign prostatic hyperplasia have led to varying estimates of prevalence in studies.

One study determined the prevalence rates of BPH in a population of 502 men aged 55 to 74 using several different case definitions. Prevalence rates in men aged 60-64 varied from 2% to 22%, depending on the parameters used. In this study, the prostate volume used as the main cut-off for diagnosis of BPH was 30cm. However, in a study using a prostate weight of 20g as the cut-off, prevalence of benign prostatic hyperplasia in men aged 60-69 was 43%.

Added to this uncertainty is the fact that many men who admit to suffering symptoms of BPH when questioned, say their symptoms are not particularly bothersome. Many men accept symptoms of benign prostatic hyperplasia as a normal part of the ageing process, and may not be prompted to seek treatment.

What are the treatment options?

Treatment options for benign prostatic hyperplasia range from no active treatment (’watchful waiting’), through various medical interventions, to surgical treatment. Each option is associated with a different balance of risks, benefits, and level of uncertainty about the long-term outcome. Treatment of BPH is directed at improving patients’ symptoms and quality of life rather than towards prevention of the serious morbidity or mortality which may rarely result. For these reasons, it is essential that patients are actively involved in the decision on which treatment they receive.

Non-drug treatment

Benign prostatic hyperplasia is not always a progressive condition. A review article summarising the results of five studies of the natural history of BPH, concluded that, of men with moderate symptoms followed for five years, 40% would improve, 45% remain unchanged and only about 15% deteriorate. One study randomly assigned 556 men with moderate symptoms of BPH to transurethral surgery or watchful waiting and followed them for almost three years. It found that only 7% of those assigned to the watchful waiting group required surgery for ‘treatment failure’. Watchful waiting is, therefore, considered a valid treatment option for men with mild to moderate symptoms.

Transurethral resection of the prostate (TURP) is considered to be the gold standard treatment for benign prostatic hyperplasia. It produces significant improvements for many men in symptoms and in objective measures, such as peak urinary flow rate. Complications which have been attributed to TURP include retrograde ejaculation, impotence, and some degree of urinary incontinence. However, the study mentioned above found no difference in rates of incontinence or impotence between men assigned to transurethral resection of the prostate and those assigned to watchful waiting.

Drug treatment

Alpha1-adrenoceptor blocking drugs act by reducing smooth muscle tone in the prostatic tissue and bladder neck, thereby decreasing resistance to urinary flow. Six agents are available in the UK; these are alfuzosin (Xatral, tablets, 2.5mg; Xatral SR, tablets, 5mg), doxazosin (Cardura, tablets, 2mg/4mg), indoramin (Doralese, tablets, 20mg), prazosin (Hypovase, tablets, 2mg; Prazosin, tablets, 2mg), tamsulosin (Flomax MR, capsules) and terazosin (Hytrin BPH, tablets, 5mg/10mg).

A review of twenty-nine clinical trials of α1-blockers stated that the average improvement in maximum urine flow rate (Qmax) with these compounds was 1.5ml/s. Overall symptom scores decreased by 14% and residual urine volume decreased by 29%. Some tolerance to the effects on urinary flow rate was noted in a proportion of patients after six months of therapy. However, the improvement in symptom scores was maintained long-term.

Side-effects associated with the α1-blockers include hypotension, particularly after the first dose, sedation, and dizziness. Therapy is usually begun with a low dose taken at bedtime and titrated upwards over a few weeks.

Tamsulosin is an agent which is more selective than other alpha1-blockers; it is said to act on the α1A-receptor subtype, which is thought to be predominant in prostatic tissue. Theoretically, such a selective action might avoid some of the cardiovascular effects seen with other agents.

Tamsulosin has been compared to alfuzosin and terazosin in clinical trials. When compared to alfuzosin in 245 men with benign prostatic enlargement and lower urinary tract symptoms suggestive of benign prostatic hyperplasia, tamsulosin produced comparable improvements in O and symptom scores over twelve weeks. Although tamsulosin had significantly less effect on both systolic and diastolic blood pressure than alfuzosin, no difference in the rate of adverse events associated with the hypotensive effects of α1-blockers was observed.

In the second study, which was single-blind, involved 72 patients and lasted for nine weeks, tamsulosin and terazosin were similarly effective in improving both subjective and objective measures of BPH. The incidence of adverse cardiovascular effects was higher in the terazosin group. It is difficult to assess how relevant the results of this study are to the UK, as it was conducted in Korea and the dose of tamsulosin was much lower than that used here.

Finasteride is a specific inhibitor of the enzyme 5a-reductase, which is responsible for the metabolism of testosterone to dihydrotestosterone, a more potent androgen. DHT stimulates prostatic growth and the development of benign prostatic hyperplasia. Treatment with 5mg finasteride for twelve months has been shown to reduce prostate volume by 19%, increase maximum urinary flow rate by 1.6ml/s, and decrease total urinary-symptom scores by 21%.

Two recent studies investigated the effects of finasteride on the incidence of acute urinary retention and the need for surgical treatment. The first study was a pooled analysis of three randomised, double-blind, multicentre studies comparing finasteride 5mg daily to placebo over 24 months in 4,222 patients with moderate symptoms of BPH. Finasteride therapy was associated with a statistically significant reduction in both acute urinary retention and rates of surgical intervention.

The second study compared 5mg of finasteride to placebo over four years in a randomised, double-blind trial. A total of 3,040 men with enlarged prostates and moderate to severe urinary symptoms were recruited from 95 centres. The primary end-point of the study was the symptom score; need for prostate surgery and development of acute urinary retention were secondary end-points.

Symptom scores decreased by a mean of 3.3 points out of 35 (9.4%) in the finasteride group, compared to a mean of 1.3 points (3.7%) in the placebo group. The risks of surgery and acute urinary retention (AUR) were both significantly reduced by finasteride. However, the absolute reduction in the risk of surgery or AUR was only 6.6%, meaning that 15 men would have to be treated with finasteride for four years in order to avoid one episode of acute urinary retention or surgery.

A recent meta-analysis of six trials comparing finasteride with placebo examined whether there was any relationship between measures of disease severity at the start of treatment and the response to finasteride. It concluded that improvements in peak urinary flow rate and symptom scores were significant only in men whose prostate volume was measured (by ultrasound or magnetic resonance imaging) at greater than 40cm3.

Adverse effects associated with finasteride include decreased libido, decreased ejaculate volume and impotence. Finasteride reduces serum concentrations of prostate specific antigen (PSA), a marker for prostate cancer, by an average of 50%.

Finasteride was compared to terazosin, combination therapy, and placebo in 1,229 men in a double-blind study lasting 52 weeks. This study found that terazosin was significantly more effective than finasteride and placebo in improving symptom scores and urinary flow rate. It also found that the combination of terazosin and finasteride was no more effective than terazosin monotherapy, even though finasteride reduced prostate size. Finasteride alone was not significantly different to placebo.

This study has been criticised on the basis of its inclusion criteria, which were based on symptoms rather than prostate size. The average prostate volume in the study population was only 37cm. An accompanying editorial suggested that men with larger prostates might respond differently to finasteride.

How should patients be managed?

The following investigations are recommended before any course of action is decided:

• full medical history,

• urinary symptom review,

• digital rectal examination (DRE),

• urine analysis, and

• serum creatinine.

Routine measurement of serum prostate specific antigen (PSA) levels is controversial. This is due to uncertainty over whether moderately raised levels are indicative of benign prostatic hyperplasia or prostate cancer. GPs should discuss policies on the use of PSA levels with local urology departments.

Symptom severity is not directly related to prostate size. Use of a validated symptom score, such as the International Prostate Symptom Score (IPSS), can help to categorise the severity of BPH, and monitor response to therapy.

Referral to a urologist for further investigations (such as ultrasound and urinary flow rate studies) and management may be considered for patients with moderate to severe symptoms, as well as those with complications such as haematuria or recurrent urinary tract infection. Clinical suspicion of prostate malignancy should also prompt immediate referral.

Alpha1-blockers may be effective regardless of the size of the prostate. Full clinical response often occurs after 4-6 weeks, while finasteride may take 6 months or more to produce maximal effects. An α1-blocker may, therefore, be an appropriate first choice therapy for many men, with finasteride reserved for those who do not tolerate α1-blockade, fail to gain relief of symptoms, or whose prostates are known to be particularly enlarged. There is no convincing evidence that any α1-blocker is more effective than another.

Conclusions

Although benign prostatic hyperplasia is common in older men, many consider the symptoms to be a normal part of the ageing process, and do not seek medical treatment. Given the variation in the natural history of the condition, and the uncertainty over the risks and benefits of most of the available interventions, there is no reason to encourage men who do not find their symptoms bothersome to seek medical intervention.

For those men whose symptoms are significantly bothersome, the use of a symptom scoring system in conjunction with clinical assessment will help to categorise severity. Those suffering from severe BPH should be offered the option of surgery, most likely by TURP. Those who decline surgery, or for whom it is not an option, may be offered drug therapy. Patients should be fully informed of the potential side-effects of all therapies, and should participate in the decision about which approach is taken.

Posted in Benign Prostatic Hyperplasia

UroXatral: Drug for Treatment of BPH

Posted by admin on April 3rd, 2010 No Comments

Trade Name Drug: UroXatral

Generic Name Drug: Alfuzosin HCl

Company: Sanofi-Synthelabo

Indication / Use: Benign prostatic hyperplasia

Approval Date / FDA Class: 12 06 2003 / 1S

Development and Mechanism of Action:Benign prostatic hyperplasia (BPH) is defined histologically. Clinically, it is characterized by lower urinary tract symptoms (urinary frequency, urgency, a weak and intermittent stream, needing to strain, a sense of incomplete emptying, and nocturia) and can lead to complications, including acute urinary retention. The mechanisms by which BPH causes symptoms and complications are unclear, although obstruction of the bladder outlet is an important factor. The best documented risk factors are increasing age and functioning testes. Estimates of the prevalence of symptomatic BPH indicate that approximately 50% of men ages 51 to 60 have benign prostatic hyperplasia. Community- and practice-based studies suggest that men with lower urinary tract symptoms can expect slow progression of the symptoms. However, symptoms can wax and wane without treatment. In men with symptoms of BPH, rates of acute urinary retention range from 1% to 2% a year. The objective of drug therapy of BPH is to reduce or alleviate lower urinary tract symptoms, to prevent complications, and to minimize adverse effects of treatment.

Table 1. Pharmacokinetics of Alpha1-Blockers
Parameter Alfuzosin
(UroXatral)		 Prazosin
(Minipress)		 Terazosin
(Hytrin)		 Doxazosin
(Cardura)		 Tamsulosin
% Oral bioavailability 49% (fed) ND ND ~ 65 > 90 (fasting)
Tmax, h ~ 8 ~ 3 ~ 1 ~ 2 ­ – 3 4 – 5 (fasting)
6 – 7 (fed)
% Protein binding ~ 90 High 90 – 94 ~ 98 94 – 99
Metabolism CYP3A4 oxidation,
O-demethylation,
N-dealkylation		 Extensive via a demethylation
and conjugation		 ND Extensive via
O-demethylation
and hydroxylation		 CYP450
Elimination T /2, h 3 – 9 2 – 3 ~ 12 ~ 22 9 – 15
Excretion Urine (10%)
Feces (75 ­ 91%)		 Bile and feces Urine (~ 40%)
Feces (~ 60%)		 Urine (~ 9%)
Feces (~ 63%)		 Urine (76%)
Feces (21%)

Pharmacotherapy for benign prostatic hyperplasia includes the 5-alpha-reductase inhibitor finasteride (Proscar), and alpha1-adrenoceptor antagonists. Finasteride reduces prostate volume and symptom scores, while increasing peak urinary flow rates. The main problem with finasteride treatment is that it increases the incidence of ejaculation disorders. Androgen receptor antagonists are of no value in BPH because of their adverse effects. Smooth muscle tone in the prostate and bladder neck is regulated by alpha1-adrenergic receptors. Blockade of these receptors can cause smooth muscle in the bladder neck and prostate to relax, resulting in an improvement in urine flow and a reduction in symptoms of benign prostatic hyperplasia. Currently available alpha1-adrenoceptor antagonists appear to possess very similar clinical efficacy producing a 15% to 25% increase in maximum flow rate with a significant improvement in 30% to 40% of patients. The non­tissue selective alpha1-blockers (prazosin, terazosin, and doxazosin) can elicit postural symptoms related to orthostatic hypotension and they may cause episodes of dizziness and somnolence as a result of distribution to and action in the CNS. Uroselective alpha1-blockers dosed on a once-daily schedule, tamsulosin (Flomax) and, most recently, alfuzosin, have been developed to address the drawbacks of the nonselective agents.

Alfuzosin (UroXatral), a tetrahydroquinazoline derivative, differs from the non­tissue selective alpha1-blockers as a result of replacement of the piperazine heterocycle in the latter with a propylenediamine moiety in the structure of the new drug. Alfuzosin is not selective for any of the alpha1-adrenoceptor subtypes (A, B, or D) but has been shown to possess a high selectivity for receptors in the lower urinary tract. At doses three to 10 times higher than those required to induce significant urethral relaxation in animal models, alfuzosin shows the lowest and shortest-lasting hypotensive activity compared to doxazosin, tamsulosin, and terazosin. Pharmacokinetics: A comparison of selected pharmacokinetic parameters of the alpha1-adrenoceptor antagonists is provided in table 1. The oral absorption of alfuzosin is significantly aided by the presence of food. The drug is extensively cleared by hepatic metabolism primarily involving the 3A4 isoform. Excretion of the drug and metabolites occurs mainly in the feces.

While there is no relationship between peak plasma concentrations of alfuzosin and age, trough levels are positively correlated with age. The concentrations in subjects 75 and older are approximately 35% greater than in those below age 65. Relative to subjects with normal renal function, the mean Cmax and AUC values for alfuzosin are increased by approximately 50% in patients with mild, moderate, or severe renal impairment. Clearance of alfuzosin is reduced in patients with moderate or severe hepatic insufficiency (Child-Pugh categories B and C), leading to threefold to fourfold higher plasma concentrations of the drug in these patients compared to healthy subjects. Therefore, alfuzosin is contraindicated in patients with moderate to severe hepatic impairment.

UroXatral: Clinical Profile

Alfuzosin (UroXatral) is officially indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia. Clinical efficacy data for alfuzosin from placebo-controlled trials have demonstrated efficacy compared to placebo in urinary flow improvement and in improvement in urinary symptoms without the need for dose titration. A randomized controlled clinical trial in 256 men compared tamsulosin against alfuzosin while a second trial in 103 men compared alfuzosin against prazosin in the treatment of BPH. These trials found no significant difference in symptom score among a-blockers tested. A clinical trial in 1,051 men comparing alfuzosin against finasteride against both drugs combined over six months found that alfuzosin compared with finasteride significantly decreased the mean international prostate symptom score from baseline, and found no significant difference between alfuzosin alone and combination therapy.

Adverse Reactions

In the clinical trials, the most common adverse effects occurring more frequently than with placebo were dizziness, upper respiratory tract infection, headache, and fatigue. Withdrawals attributed to adverse events have been found to be similar for alfuzosin, tamsulosin (0.4-mg dose), and placebo. However, a higher withdrawal rate was found with doxazosin, terazosin, and tamsulosin (0.8-mg dose). There was little observable difference between the number of men experiencing dizziness with alfuzosin or tamsulosin compared with placebo. However, more men experienced dizziness after terazosin and doxazosin than placebo. Comparison of tamsulosin versus alfuzosin found similarities in the incidence of common adverse effects including dizziness (7%), asthenia (2%), and postural hypotension (2%).

As with other a-blockers, some patients may experience postural hypotension or syncope. If symptoms of angina pectoris should appear or worsen, the use of alfuzosin should be discontinued. Caution should be exercised when alfuzosin is administered in patients with severe renal insufficiency. Consideration should be given in deciding to prescribe alfuzosin for patients with a known QT prolongation or who are taking medications known to prolong QT, although there has been no signal of torsades de pointes in extensive postmarketing experience with alfuzosin outside the United States.

Drug Interactions

Clearance of alfuzosin (UroXatral) via CYP3A4 metabolic pathways results in interactions between the new drug and other drugs that either inhibit or induce this enzyme. Repeated administration of 400 mg of ketoconazole, a potent inhibitor of CYP3A4, increased alfuzosin Cmax 2.3-fold and AUC increased 3.2-fold following a single 10-mg dose of alfuzosin. Therefore, alfuzosin should not be coadministered with potent inhibitors of CYP3A4, eg, ketoconazole, itraconazole, or ritonavir, because exposure is increased. Coadministration of alfuzosin with antihypertensive medications may enhance the effects of the latter on blood pressure.

Dosage and Administration

UroXatral (alfuzosin) hydrochloride is formulated as a 10-mg extended release tablet. The recommended dosage is one 10-mg extended-release tablet daily to be taken immediately after the same meal each day. The tablets should not be chewed or crushed.

Posted in Drugs: α-blockers

Selective and non-selective α-blockers for BPH: Application

Posted by admin on March 31st, 2010 No Comments

Application to clinical practice

An important issue is extrapolation of the results of alfuzosin (Uroxatral) to the terazosin (Hytrin) we prescribe in Canada. Although the affinity αa/αb receptor ratio is similar for alfuzosin and terazosin, their incidence of association with signs of hypotension differ. In placebo-controlled trials, patients treated with terazosin experienced obvious signs of hypotension, whereas incidence among patients receiving tamsulosin (Flomax) and alfuzosin (Uroxatral) was similar to that among patients treated with placebo. This indirect comparison between α-blockers has, of course, important limitations but should be borne in mind when extrapolating results to terazosin (Hytrin).

Two trials have directly compared tamsulosin (Flomax) with terazosin (Hytrin). One single-blind trial was conducted among Asian men with high-normal blood pressure levels and symptomatic benign prostatic hyperplasia (BPH). They received 0.2 mg of tamsulosin (half the dose white men would receive) or 5 mg of terazosin daily. Both groups experienced significant improvement in Qmax and symptom scores, but the number of side effects and the reduction in standing blood pressure levels from baseline (-16.1/-11.4 mmHg for the terazosin group vs -9.4/-5.4 mmHg for the tamsulosin group) was statistically greater in the terazosin group. The authors did not mention whether lowering blood pressure levels had an effect on symptoms. The other trial included normotensive healthy men, only half of whom had BPH. Patients were randomized in a double-blind fashion to receive 0.4 mg of tamsulosin (Flomax) or 5 mg of terazosin (Hytrin) daily. Significantly more patients treated with terazosin experienced symptomatic hypotension, but there was no difference in the proportion of patients experiencing asymptomatic hypotension. No differences were observed in blood pressure. These two studies have several important limitations, namely the smaller tamsulosin dose used and the fact that some patients did not have benign prostatic hyperplasia. The results, however, when interpreted with results of the placebo-controlled trials, support some of the findings of the alfuzosin-tamsulosin trial. These findings include a lower incidence of signs of hypotension in normotensive and hypertensive patients receiving tamsulosin and, possibly, no significant decrease in blood pressure in patients with high-normal (or stage 1) hypertension in the tamsulosin group.

Several categories of patients with symptomatic BPH can present a treatment dilemma: hypertensive patients already stabilized using other antihypertensive medications, normotensive patients, normotensive patients receiving other antihypertensive agents for other indications (eg, an angiotensin-converting enzyme inhibitor [ACE-I] for diabetic nephropathy), and patients for whom suboptimal doses of α-blockers reduce benign prostatic hyperplasia symptoms but cause hypotensive side effects. For these patients, an attempt to initiate or reinstitute a non-selective α-blocker with more frequent follow-up visits and a very slow titration of dose could be tried, or tamsulosin could be initiated, provided patients can afford it (approximately $36/month). The costs of tamsulosin (Flomax) and terazosin (Hytrin) are similar, but only terazosin is covered on most provincial drug plans.

Two important benefits can be derived from using tamsulosin (Flomax). First, because the dose does not need to be titrated, there is less risk of confusion for patients and fewer follow-up visits. Second, the possibility of a faster onset of action would mean a faster improvement in quality of life for patients.

Several questions, such as whether tamsulosin also has a favourable effect on lipids, whether it decreases risk of falls, and what its long-term effects are, remain unanswered.

Bottom line

• Tamsulosin (Flomax), a uroselective α-blocker, at a dose of 0.4 mg, appears to be as effective as alfuzosin (Uroxatral), a non-selective α-blocker. Unlike terazosin (Hytrin), the dose of tamsulosin does not need to be titrated. Tamsulosin (Flomax) produced slightly fewer symptoms of hypotension, but this did not translate into clinical outcomes, such as more falls. These benefits might not be important because terazosin is now available in starter packs to assist patients to titrate the dose themselves.

• Patients who already have good blood pressure control with other preferable agents (eg, diabetics receiving ACE-Is) and who had severe hypotensive effects with non-selective α-blockers might prefer a uroselective agent.

• Most of our patients with benign prostatic hyperplasia are also at risk for hypertension, and a non-selective α-blocker treats both conditions with one pill. Differences between the two treatments were small, and patient-oriented outcomes were similar.

• Tamsulosin (Flomax) is slightly more expensive and does not seem to confer greater benefits for most of our patients.

Posted in Drugs: α-blockers

Selective and non-selective α-blockers for BPH

Posted by admin on March 28th, 2010 No Comments

Relevance to family physicians

Symptomatic benign prostatic hyperplasia (BPH) is a common condition encountered in about 50% of male patients older than 50. Prevalence increases with age. In the last few years, pharmacologic treatment and watchful waiting have played an increasing role in treating symptomatic BPH. Until recently, pharmacologic options were limited to non-selective α-blockers and finasteride (Proscar). Non-selective α-blockers are usually first-line agents because their onset of action is fast (4 to 6 weeks); their efficacy is maintained, especially in patients with smaller prostates; and they are not expensive. Non-selective α-blockers, initially developed to treat hypertension, can cause side effects, such as postural hypotension, dizziness, headache, palpitations, and syncope.

Tamsulosin (Flomax), a selective α-blocker, has been commercially available in Canada since June 1998. Because it is more urospecific than other α-blockers, it has less potential for causing symptomatic hypotension. The dose of tamsulosin does not need to be titrated and this might, therefore, decrease the frequency of follow-up visits and result in a faster onset of action. In this trial, tamsulosin is compared with alfuzosin (Uroxatral), which is roughly comparable to the terazosin (Hytrin) commonly prescribed in Canada.

Overview of study and outcomes

A total of 245 men at least 45 years old entered the study. Main inclusion criteria were a Boyarsky score >6 and a maximum urinary flow (Qmax) of <12mL/s and >4mL/s.

The Boyarsky system score is a symptom-assessment tool used to evaluate the severity of nocturia, frequency, hesitancy, intermittency, terminal dribbling, urgency, impairment of size and force of stream, dysuria, and sensation of incomplete voiding. The system allows 0 to 3 points for each of nine questions for a maximum of 27 points. Patients scoring < 7 points are considered mildly symptomatic; 8 to 19 points moderately symptomatic; and > 20 points severely symptomatic.

Main exclusion criteria for the trial were coexisting conditions affecting micturition, previous pelvic region surgery, and concomitant medications acting on the prostate (eg, anticholinergic drugs). After a 2-week placebo run-in period, patients were randomized to alfuzosin (n = 119) or tamsulosin groups (n = 126). Primary outcome variables, Qmax, and total Boyarsky score were measured at weeks 2, 6, and 12. Secondary outcome variables included irritative, obstructive, and individual symptom Boyarsky score; tolerability; and lifestyle issues. Intention-to-treat analysis was performed, and all statistical tests were two-sided.

Results

Tamsulosin (Flomax) and alfuzosin (Uroxatral) had similar strong effects on Qmax, which increased by 1.6 mL/s, and on total Boyarsky score, which decreased by 4.1 and 3.8 points, respectively. Maximum urinary flow was achieved within 2 weeks with tamsulosin and between 2 and 6 weeks with alfuzosin.

For the secondary end points, no difference was observed in the lifestyle questionnaire score or Boyarsky obstructive, irritative, and individual symptom scores between the two groups. Hypotensive effects, such as dizziness, headaches, palpitation or tachycardia, syncope, and postural hypotension, were experienced by 9.2% of patients in the tamsulosin group and 10.5% of patients in the alfuzosin group (P=.442). All other side effects, attributed to the drug or not, were not statistically significantly different between groups (53% vs 43%, P= .826).

At baseline in the tamsulosin group, mean supine blood pressure level was 143.9/85.7 mm Hg and mean standing blood pressure level was 141/88 mm Hg. At the end, there was no significant reduction of mean blood pressure levels in the tamsulosin group (-0.9 mmHg for supine and standing systolic blood pressure and +0.3 and -1.8 mmHg for supine and standing diastolic blood pressure). In the alfuzosin group, mean baseline supine blood pressure level was 146.1/88.5 mm Hg, and mean baseline standing blood pressure level was 142.9/88.6 mm Hg. A significant change from baseline in supine and standing systolic blood pressure level of-5.3 and -3.6 mm Hg, respectively, and in supine and standing diastolic blood pressure level of -3.6 and -4.5 mmHg, respectively, were observed. Differences between the groups were 4.4 mmHg for systolic and 2.7 to 3.9 mmHg for diastolic blood pressure level at end point (P≤.05). The authors did not explain whether these differences had an effect on symptoms.

Subgroup analysis showed that patients aged 65 or older (n=57) in the alfuzosin group experienced larger blood pressure level reductions than patients that age (n = 59) in the tamsulosin group. Changes of-0.1 to -1.0 in systolic and +0.6 to -0.8 in diastolic pressure levels were seen in the tamsulosin group; changes of -8.6 to -9.7 mmHg (systolic) and -5.4 and -6.2 mmHg (diastolic) were seen in the alfuzosin group. Differences in mean blood pressure levels from baseline to end point between the treatment groups were almost 9 mm Hg (systolic) and 5 mm Hg (diastolic) (P= .016). Normotensive patients in the alfuzosin group had greater supine blood pressure level reductions than those in the tamsulosin group (P=.029). Again, the authors did not elaborate whether these differences were in symptoms. No significant differences between the two treatment arms could be observed in patients younger than 65 years (n= 131) or in hypertensive patients (n=59).

Analysis of methodology

The study was well designed, but the omission of use ful information made it difficult to interpret and apply the results to a specific patient population. For example, patients’ baseline characteristics were not reported, and the lifestyle questionnaire was not described. Also, the exact onset of action of tamsulosin (Flomax) could not be determined because the first follow-up visit was 2 weeks after initiation of treatment. Finally, measuring patients’ and their partners’ satisfaction would have been helpful for using the results in the context of clinical practice.

Posted in Drugs: α-blockers

Terazosin (Hytrin), finasteride (Proscar), or both in BPH

Posted by admin on March 21st, 2010 No Comments

Glossary

Adrenergic: Relating to nerve cells of the autonomic nervous system. Alpha- and beta-adrenergic receptors receive chemical signals controlling autonomic functions. Adrenergic blockers prevent signals from being received by that class of receptor.

Androgen: Any male sex hormone, such as testosterone.

Prostatectomy: Surgery to reduce the size of the prostate gland.

Benign prostatic hyperplasia (BPH) most often manifests as obstructed urinary flow and irritative urinary symptoms. Treatments are aimed primarily at relieving such symptoms. Prostatectomy and watchful waiting are the long-accepted therapies. Two types of drug have recently been added to the therapeutic options for BPH and have been demonstrated to be safe and effective in previous studies. They have not, however, ever been compared against one another in a blinded study.

This study enrolled 1,229 men with symptoms of BPH who were attending outpatient clinics at participating Veterans’ Affairs medical centres in the United States between 1992 and 1994. They were between 45 and 80 years old, had symptom scores on the American Urological Association Symptom Index of at least eight, and a mean peak urinary flow rate of between 4 ml and 15 ml per second. After undergoing physical and laboratory exams and receiving placebo for four weeks, the men were assigned to one of four drug regimens. They received either placebo, terazosin (Hytrin) (10 mg/day), finasteride (Proscar) (5 mg/day) or a combination of the two drugs for 52 weeks.

Participants were examined at regular intervals over the course of the study, and pills were counted to assess compliance with the prescribed drug regimen. Men receiving terazosin (or its placebo) could have the dose reduced to 5 mg/day if they experienced ill effects at 10 mg. Side effects were inquired about at each follow-up visit. Patients receiving finasteride had significantly more problems with impotence and decreased sex drive, while those on terazosin reported dizziness more often and those receiving the combination reported more problems with ejaculation. In all, 18% of the patients discontinued their treatment before the end of the study for various reasons. However, only 4.8% of the finasteride group, 5.9% of the terazosin group and 7.8% of the combination group stopped taking their medication due to adverse effects — as well as 1.6% of those on placebo.

At the end of the study period, test results and symptom scores were compared to those recorded at the outset of the study, and the changes noted in each group were compared against each other. Mean symptom scores were decreased almost twice as much in the terazosin and combination groups as in the finasteride group, with the placebo group having an even smaller reduction. Mean increases in peak urinary flow rates were 1.4 ml/second for placebo, 1.6 ml/sec for finasteride, 2.7 ml/sec for terazosin and 3.2 ml/sec for the combination group. Prostate volume was found to increase by 0.6 cm3 in the placebo group and 0.5 cm3 in the terazosin group, while decreasing by 6.1 cm3 in the finasteride group and by 7.0 cm3 in the combination group. Prostate-specific antigen (PSA, a common measure of prostate health) levels were more improved in the terazosin and combination groups.

Given that the primary goal of treatment is to alleviate benign prostatic hyperplasia (BPH) symptoms, the authors concluded that the comparison of the two drugs clearly favoured terazosin. Terazosin produced significantly better improvements in symptom scores and urinary flow rates. As well, there appeared to be no advantage to taking finasteride and terazosin in combination, as results were not significantly better than in men receiving terazosin alone.

The finding that finasteride was no better than placebo contradicts other studies that looked at finasteride alone. The authors suggest that this may be due to the fact that different indexes of symptom scores were used, or that participants in the other studies had a higher degree of prostate enlargement at the outset. A longer study period may also have affected the outcome. As is so often the case with medical research, more studies need to be done so that all the possible variables can be accounted for before there are definitive answers.

Posted in Drugs

What is the best medical treatment for BPH?

Posted by admin on March 7th, 2010 No Comments

Lepor H, Williford WO, Barry MJ, Brawer MK, Dixon CU.
The efficacy of terazosin, finasteride or both in benign prostate hyperplasia.
 N Engl J Med 1996; 335:533-9.

Research question

There are two main types of medications for the treatment of benign prostate hyperplasia (BPH): the first are α-adrenergic-antagonist drugs (eg, terazosin) that relax the smooth muscle in the prostate and the second are 5-α-reductase inhibitors (eg, finasteride) that block formation of dihydrotestosterone and thereby shrink the prostate. Which works better? Does a combination of the two drugs work best?

Type of article and design

Randomized, controlled trial of therapy.

Relevance to family physicians

In the last few years you could hardly open a medical journal without being bombarded with information about finasteride (Proscar). Many of us were using terazosin (Hytrin) also to treat BPH patients who had symptoms or were tired of “watchful waiting.” Terazosin is cheaper, is covered on most provincial formularies, and works faster, but we often wondered which drug was more effective and whether a combination could be used for treatment-resistant cases to prevent surgery. In the United States in 1990, more than 329000 men had transurethral prostatectomies (TURPs). A TURP is very effective but patients are understandably concerned about the side effects of surgery. Benign prostatic hyperplasia is extremely common and becomes more common with age. It can have a deleterious effect on quality of life, especially in the context of such conditions as chronic disease and depression.

Overview of study and outcomes

This study recruited 1686 men, aged 45 to 80 years, who had symptomatic benign prostate hyperplasia and were seen at Veterans Affairs medical centres. During a 4-week lead-in time, the men received a placebo and were evaluated twice using the American Urological Association’s (AUA) symptom index; to be eligible, men had to score at least 8 points out of 35.

Uroflometry, residual volume after voiding, serum concentrations of prostate-specific antigen (PSA), urine culture and sensitivity, and transrectal ultrasound examinations were all performed. No threshold level of prostatic enlargement was required (which fits with current evidence that severity of BPH is not simply a function of size). Exclusion criteria were use of similar medications to those being tested, symptoms of severe coronary artery disease, orthostatic hypotension, prostate cancer, history of prostate surgery, and active urinary or kidney disease. This left 1229 men (73% of those recruited) who were mostly white, averaged approximately 65 years old, had prostatic volumes of 37 cm3, had PSAs of 2 to 3, and had AUA symptom scores of an average 16 out of 35.

Results

The men at each site, randomized to finasteride, terazosin, combination therapy, or placebo, were evaluated at 2, 4, and 8 weeks and then every 6 weeks for 1 year for AUA symptom scores and peak urinary flow rates. Symptom scores in each of the four groups had decreased at 1 year by 2.6 (placebo), 3.2 (finasteride), 6.1 (terazosin), and 6.2 (combination) points (P < 0.001). Peak urinary flow rates had increased by mean values of 1.4, 1.6, 2.7, and 3.2 mL/sec, respectively (P < 0.001). Adverse effects caused 1.9% of the placebo group, 6.2% of the finasteride group, 7% of the terazosin group, and 9.4% of the combination group to drop out. As expected, dizziness was significantly more frequent in the terazosin group. Impotence and decreased libido were significantly more frequent among finasteride subjects. Combination therapy had these side effects and significantly more ejaculatory abnormalities.

Analysis of methodology

This sophisticated, four-arm, randomized trial had good follow up and compliance. Groups were similar at the start of the trial and were treated equally with intention-to-treat analysis.

Application to clinical practice

This study is interesting in that it tells us that a drug that many physicians are prescribing is no better than placebo.

This conflicts with some previous data, and the editorial accompanying the study tells why: benign prostate hyperplasia is not a homogeneous process and size does not predict symptoms. This study had no threshold size of prostate whereas the previous two studies positive for finasteride were restricted to men with larger prostates (60 mL2 and 47 mL2, respectively). Given the mechanism of shrinking or debulking with finasteride, those with larger prostates might well do better than they did with placebo.

What is the clinical significance of a 3- to 4-point reduction out of 35 in an AUA symptom score? It might be worthwhile for patients with severe symptoms who are getting up at night repeatedly to urinate, but perhaps not for patients with milder symptoms who wish to avoid the adverse effects of terazosin. Including some patient-oriented outcomes might have been helpful to further assess the benefits of treatment against the adverse effects of medications. Quality-of-life measurements might have been helpful also to assess how lower scores and increased flow allowed better social functioning, especially for elderly or chronically ill men.

Bottom line

Terazosin is probably the first-line drug of choice for benign prostate hyperplasia given its effectiveness, low cost, and rapid action.

Finasteride did no better than placebo in this trial. Patients who are treatment resistant and have large prostates might choose finasteride as a final alternative if they wish to delay surgery. The mixed results of this trial indicate the heterogeneous nature of this disease process and dispel the myth that all symptoms of BPH are simply the result of an enlarging prostate.

Posted in Book review

Pharmacotherapy for BPH (Benign Prostatic Hyperplasia)

Posted by admin on March 3rd, 2010 No Comments

Mechanisms of Obstruction and Rationale for Pharmacotherapy

Current pharmacotherapy for Benign Prostatic Hyperplasia (BPH) is based on agents that relax the smooth muscles of prostatic urethra and stroma and those that deprive acinar cells of androgen.

Various agents have been tried in the treatment of BPH (Table). They may be broadly grouped into those affecting the dynamic component of urethral obstruction, namely the smooth muscle and prostatic stroma, and those affecting the glandular elements by androgen deprivation. The mechanism of action of many agents claimed to be useful in Benign Prostatic Hyperplasia is not clearly understood.

TABLE — Drugs That Have Been Tried in the Medical Management of Benign Prostatic Hyperplasia
(Some agents act by more than one mechanism)
Drug Class Drug (Code Designation) Trade Name
α1-Adrenergic antagonists
Prazosin HCl Minipress
Terazosin HCl Hytrin
Doxazosin mesylate Cardura
Phentolamine mesylate
YM-617
Nicergoline Sermion
Indoramin Baratol
Ketanserin
Yohimbine HCI
Antiandrogens
Selective
5α-Reductase inhibitors Finasteride Proscar
Epristeride
Agents blocking androgen uptake and causing receptor blockade Flutamide Eulexin
Cyproterone acetate
Nilutamide Nilandron
Oxendolone Prostetin
Gestonorone caproate Depostat
Casodex (10176,334)
Nonselective
Gn-RH analogues Nafarelin acetate Synarel
Leuprolide acetate Lupron
Goserelin acetate Zoladex
Estrogens Diethylstilbestrol
Chlorotrianisene TACE
Progestational agents Megestrol acetate Megace Primostat
Hydroxyprogesterone acetate
Hydroxyprogesterone caproate
Medrogestone
Aromatase inhibitors Testolactone Teslac
Atamestane
Steroidogenesis inhibitors Aminoglutethimide
Ketoconazole Nizoral
Prolactin inhibitor Bromocriptine mesylate
Miscellaneous agents Candicidin
Sitoglustde (WA184)
Probucol
Cimetidine Tagamet
Physosterols
Extract of the plant Serenoa repens Permixon
Spironolactone Aldactone
Tamoxifen citrate
Bazoton
Fluorouracil
Gn-RH – gonadotropin-releasing hormone, HCl – hydrochloride

Caine has suggested that obstruction due to Benign Prostatic Hyperplasia occurs because of two factors: a dynamic component is thought to occur as a result of the contraction of smooth muscles of the prostate and prostatic urethra and is mediated mostly by adrenergic receptors; and a mechanical component of obstruction is related to the presence of a mass of hyperplastic acinar or stromal tissue that compresses and narrows the urethral lumen. There is some evidence that the presence and density of stromal content in BPH may relate to the severity of obstruction.

Current understanding of the biologic mechanisms of obstruction is limited and does not extend to two common clinical facts. The first is that the size of the prostate does not always correlate with the severity of symptoms or objective signs of obstruction. The second is the discrepancy between the histologic changes of BPH and the presence and severity of symptoms. From a physiologic standpoint, five conditions in patients with symptoms of “BPH” may exist singly or in combination. These are prostatic urethral obstruction, impaired detrusor contractility, detrusor instability, sensory urgency, and primary vesical neck obstruction. All these conditions likely result from varying combinations of prostatic enlargement and subtle neurologic dysfunction, all due to age-related central nervous system degeneration. Alternatively, a hyperplastic prostate during growth may disrupt normal sphincteric function. Thus, it is not surprising that prostatectomy fails to relieve symptoms of prostatism in about 20% of patients because the symptoms may be caused by poorly understood deficits in neurosensory pathways regulating micturition and sphincteric function.

Transurethral prostatectomy is the most common surgical procedure currently performed for the treatment of Benign Prostatic Hyperplasia. Outcome analyses have questioned the results of transurethral resection of the prostate (TURP). Patients undergoing TURP have been reported to be at greater risk from cardiovascular death than patients undergoing open prostatectomy. Recently these findings were disputed, and it was reported that transurethral resection for BPH does not increase long-term mortality and that comorbid illnesses and older age probably account for the apparent increase in long-term mortality after TURP. The morbidity of the procedure remains unchanged, however. In a review in 1962, the morbidity after transurethral resection of the prostate was reported to be 18% and the mortality 2.5%. More recently, the American Urological Association (AUA) cooperative study of 3,885 patients after the procedure revealed an overall complication rate of 18% and 0.2% mortality. Thus, the search for alternative therapies has been prompted by patients’ preferences for less invasive forms of treatment without prohibitive side effects. Apart from pharmacotherapy, other methods undergoing trials for the treatment of Benign Prostatic Hyperplasia include laser ablation, microwave hyperthermia, and prostatic stents. Ultimately, the role of surgical treatment and newer modalities must be based on relative effectiveness, cost, morbidity, effect on quality of life, expectations, and treatment preferences of patients.

Posted in Pharmacotherapy

Management of Benign Prostatic Hyperplasia (BPH): Pharmacotherapy

Posted by admin on February 14th, 2010 No Comments

Pharmacologic agents designed to relax prostatic smooth muscle (alpha-adrenergic blockers) and reduce prostatic size (androgen suppression) have been reported to be safe and effective in treating benign prostatic hyperplasia (BPH). The selective alpha-1 blockers doxazosin and terazosin, and the 5-alpha reductase inhibitor finasteride, have been approved by the FDA for the treatment of BPH. Patients with clinically significant BPH are candidates for pharmacotherapy unless they are experiencing severe symptomatology (e.g., serious urinary retention). These agents are reported to improve symptoms of benign prostatic hyperplasia (BPH) with minimal morbidity at a substantial cost savings relative to TURP.

Pharmacotherapy: Alpha-Adrenergic Blockers

Alpha-1 adrenergic blockers prazosin (Minipress), terazosin (Hytrin) and doxazosin (Cardura) have all been extensively studied in patients with benign prostatic hyperplasia (BPH). These agents relax smooth muscle at the bladder neck and prostatic urethra, offering symptomatic improvement in a relatively short period of time.

Although prazosin has demonstrated efficacy in patients with BPH, it has fallen out of favor since it is short-acting, requiring multiple daily dosing. Terazosin has been studied extensively and has consistently demonstrated efficacy. Patients on terazosin, frequently titrated to doses of 10 mg once daily, show an increase in peak urinary flow rate (PUFR) and a decrease in their symptoms. Doxazosin, although not studied as extensively as terazosin, has also demonstrated similar efficacy in this patient population. Similar agents studied outside the United States, such as tamsulosin and alfuzosin, have demonstrated some efficacy.

The long-acting alpha-1 blockers terazosin and doxazosin are frequently used to treat common comorbid disease states such as hypertension. Occasionally, however, the maximum dose of an alpha-1 blocker necessary to treat benign prostatic hyperplasia (BPH) in normotensive men cannot be achieved due to the risk of hypotension developing. However, studies have demonstrated that alpha-1 blockade will significantly lower blood pressure in patients with BPH who are hypertensive; yet in normotensive BPH patients, the blood pressure is not significantly decreased. Common dosages employed for alpha-1 antagonists in BPH and hypertension can be found in Table 3. Additionally, alpha-1 blockers have a favorable effect on the lipoprotein profile by slightly lowering LDL and VLDL, and increasing HDL, thereby decreasing the risk for coronary artery disease.

Table 3 Common Dosages Utilized for Alpha-1
Antagonists in BPH and Hypertension
Drug Dose for BPH Dose for Hypertension
Prazosin 2 mg BID to TID 6 mg to 15 mg divided 2 to 3 times daily
Doxazosin 2 mg to 8 mg QD 2 mg to 16 mg QD
Terazosin 5 mg to 10 mg QD 2 mg to 5 mg QD

Approximately 10%–15% of patients receiving an alpha-1 blocker develop a clinically significant adverse event. Side effects such as dizziness, headache, asthenia, syncope and hypotension have been reported, especially after the first dose. In order to minimize this “first dose” effect, it is important to take the once-daily dose at bedtime, titrating upwards slowly.

Posted in Management

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