Health and Prostate

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.

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.