Introduction

Although benign prostatic hyperplasia (BPH) is the most prevalent urologic disorder among elderly men,¹ its pathophysiology remains unclear. Until recently, the prevailing hypothesis was that the voiding (obstructive) and storage (irritative) symptoms of BPH resulted from the combined effects of prostate enlargement (the static component) and ₁-adrenoceptor-mediated increased prostatic smooth muscle tone (the dynamic component).¹ Thus, the efficacy of ₁-adrenoceptor antagonists in relieving symptoms of BPH was generally attributed to inhibition of ₁-adrenoceptors in the smooth muscle of the prostate gland and bladder neck, resulting in amelioration of bladder outlet obstruction.^{2, 3}

However, there is no correlation between the severity of lower urinary tract symptoms (LUTS) and prostate size or measures of bladder outlet obstruction (urinary peak flow rate, postvoid residual volume).^{4, 5, 6} Furthermore, even after obstruction is relieved by prostatectomy, storage symptoms often continue.⁷ Recent experimental data suggest the involvement of a central mechanism of action of ₁-adrenoceptor antagonists in the mediation of LUTS relief, particularly with respect to storage symptoms.⁸ In addition, results of an analysis of adverse event data from the Veterans Affairs cooperative study suggest that dizziness and asthenia associated with ₁-adrenoceptor antagonists may not be due to vascular events.⁹

As with BPH, blood pressure tends to increase with advancing age;^{10, 11} BPH and hypertension occur concomitantly in an estimated 25% of men older than 60 y of age.¹² Because of the involvement of postsynaptic ₁-adrenoceptors in the mediation of increased peripheral vascular resistance and elevated blood pressure,¹³ pharmacologic ₁-adrenoceptor blockade has proven to be an effective treatment approach in patients with hypertension.¹⁴ The involvement of ₁-adrenoceptors in the pathophysiology of hypertension and BPH provides a common target for drug treatment in patients who present with both conditions, a strategy that could simplify treatment regimens and reduce treatment costs.

Doxazosin is a selective ₁-adrenoceptor antagonist that provides efficacy in the treatment of patients with mild-to-moderate hypertension and BPH.¹⁴ A new long-acting, controlled-release gastrointestinal therapeutic system (GITS) formulation allows gradual gastrointestinal absorption of the drug. This GITS formulation diminishes the fluctuations between maximum and minimum plasma drug concentrations observed with the standard formulation.^{15, 16} As a result, doxazosin GITS therapy can be initiated at a therapeutic dose of 4 mg compared with the usual initial dose of 1 mg with standard doxazosin, thus simplifying the dose titration schedule. Doxazosin GITS is as effective as standard doxazosin in the treatment of hypertension^{16, 17, 18, 19, 20} or BPH.^{18, 21, 22, 23}

Although the blood pressure-lowering effect of doxazosin is a therapeutic advantage in patients with comorbid BPH and hypertension, it has been erroneously perceived as less desirable in normotensive men. However, the degree of blood pressure lowering with doxazosin differs markedly in hypertensive and normotensive patients. The magnitude of the decrease in normotensive patients, although statistically significant, is not clinically significant.

The blood pressure-lowering effects of doxazosin in the treatment of BPH patients who have normal blood pressure and in those who have hypertension and BPH comorbidly are reviewed here. Because the results of treatment may be statistically significant for both groups, the differences will also be described as clinically important or unimportant.

Blood pressure effects in hypertensive patients with BPH

Kirby reported an integrated analysis of two double-blind, placebo-controlled studies comparing the effect of doxazosin (standard formulation) on sitting blood pressure in 232 men between 50 and 80 y of age with symptomatic BPH with or without concomitant hypertension.²⁴ Men were classified as either hypertensive (defined as a sitting diastolic blood pressure (DBP) >90 mmHg; n=51) or normotensive (DBP 90 mmHg; n=173). Patients were randomized (after a washout period of 1 week) to treatment with doxazosin or placebo for 9–12 weeks. Treatment with doxazosin (1 mg/day titrated up to 4 mg/day) produced similar improvements in maximum urinary flow rate in the hypertensive and normotensive patient groups. However, doxazosin had differing but expected effects on sitting blood pressure in the two groups. In hypertensive patients, doxazosin treatment produced statistically significant and clinically important reductions from baseline in sitting blood pressure (systolic blood pressure (SBP)/DBP -19/-10 mmHg) compared with minimal reductions from baseline in placebo-treated patients (SBP/DBP -2/-7 mmHg) as shown in Figure 1. Patients treated with doxazosin had a greater reduction in SBP (P=0.019) and DBP (P=0.001) compared with placebo.²⁴ No statistically significant or clinically important changes in mean sitting heart rate were observed in the hypertensive patients treated with doxazosin. Hypertensive patients receiving placebo, however, had a statistically significant decrease in sitting heart rate (-6.44 bpm; P=0.02 vs baseline).

Figure 1.

Changes in sitting SBP and DBP in hypertensive and normotensive patients after 9–12 weeks of treatment with doxazosin. Between-group P-values: DBP<0.001; SBP=0.019. Reprinted with permission from Kirby.²⁴

Full figure and legend (48K)

Another multicenter, community-based, 8-week, open-label study (Hypertension and BPH Intervention Trial (HABIT)) evaluated the efficacy of doxazosin therapy in 491 patients with comorbid BPH and hypertension.²⁵ Because this was a community-based study, it approximated the experience encountered in everyday clinical practice. Of 491 patients, 236 were 65 y of age, and 255 were between 45 and 64 y of age. At baseline, the study patients were divided into four groups according to blood pressure status: 'treated/well controlled' (sitting DBP <90 mmHg), 'treated/poorly controlled' (sitting DBP 90 mmHg despite antihypertensive drug treatment), 'untreated/hypertensive' (sitting DBP 90 mmHg), and 'untreated/normotensive' (normotensive despite a history of hypertension). The doxazosin dose was titrated during 5 weeks to doses that provided optimal control of blood pressure and BPH symptoms, up to a maximum of 16 mg/day. The patients were then maintained on the established optimal dose for 8 weeks. After 8 weeks of maintenance treatment, mean daily dosages were 7.2 mg for 'treated/well controlled,' 9.2 mg for 'treated/poorly controlled,' 8.0 mg for 'untreated/hypertensive,' and 7.6 mg for 'untreated/normotensive.' In all patient groups, doxazosin treatment significantly improved BPH symptoms, regardless of the degree of severity of urinary symptoms (P<0.001 vs baseline).

Eight weeks of doxazosin treatment resulted in statistically significant mean reductions from baseline in sitting and standing SBP and DBP (P<0.001) in all patient groups. However, the reductions were of clinical importance only in patients who were hypertensive at baseline, with mean reductions in sitting and standing SBP of 14–20 mmHg and in sitting and standing DBP of 11–13 mmHg, respectively (Table 1).

Table 1 - Effects of doxazosin treatment on blood pressure at 8 weeks in patients with BPH grouped according to blood pressure status at baseline.

Full table

Among the patients with poorly controlled hypertension at baseline despite antihypertensive drug treatment ('treated/poorly controlled' group), addition of doxazosin achieved the goal blood pressure (SBP <140 mmHg; DBP <90 mmHg) recommended by the Joint National Committee (JNC) guidelines^{26, 27} in 73% of patients receiving angiotensin-converting enzyme inhibitors, 42% of those receiving calcium channel blockers, and 56% of those receiving combination therapy with drugs from two antihypertensive classes.

Treatment-related postural dizziness occurred in 2% of patients, and treatment-related postural hypotension occurred in 1% of patients. Discontinuation rates due to adverse events were slightly lower among normotensive patients than hypertensive patients. The discontinuation rates in the 'treated/well controlled' and 'untreated/normotensive' groups were 6.3 and 5.6%, respectively, compared with rates of 11.3% and 8.1% in the 'treated/poorly controlled' and 'untreated/hypertensive' groups, respectively.

A double-blind, placebo-controlled, dose–response study²⁸ and a long-term, open-label extension of this study²⁹ demonstrated a significant blood pressure-lowering effect of doxazosin therapy in patients with BPH and concomitant hypertension. In the multicenter, double-blind, placebo-controlled, dose–response study, 248 patients (aged 45 y) with symptomatic BPH and mild-to-moderate hypertension (baseline sitting DBP of 90–114 mmHg) were randomized to doxazosin 2 mg (n=39), 4 mg (n=46), 8 mg (n=45), or 12 mg (n=45) or placebo (n=41) for a 14-week period, following a 2-week placebo run-in period.²⁸ Overall, doxazosin improved urinary flow rates and scores for total, obstructive, and irritative BPH symptoms. Statistically significant and clinically important mean reductions were observed in sitting and standing SBP and DBP measured at plasma trough concentrations following 4-mg, 8-mg (DBP only), and 12-mg daily dosages of doxazosin compared with placebo. Over the 2–12-mg/day doxazosin dosage range, similar mean reductions were seen in standing SBP/DBP (-11.6 to -17.4/-9.8 to -12.7 mmHg) and sitting SBP/DBP (-9.1 to -16.1/-9.6 to -11.7 mmHg). In comparison, the mean reductions in standing and sitting SBP/DBP observed following treatment with placebo were -3.4/-4.3 and -2.8/-4.5 mmHg, respectively (P<0.05 for comparisons with doxazosin). Slight, comparable changes in heart rate occurred in the doxazosin and placebo treatment groups. Mild-to-moderate hypotension (all causality) occurred in only five of 199 (2.5%) patients treated with doxazosin.

A total of 178 hypertensive BPH patients who completed the double-blind, placebo-controlled portion of the study mentioned above²⁸ were enrolled in a long-term, open-label extension, 28 of whom completed 4 y of open-label doxazosin treatment at fixed daily dosages ranging from 4 to 16 mg/day.²⁹ This study demonstrated that the efficacy of doxazosin treatment for both BPH and diastolic hypertension was maintained with 4 y of continuous treatment. Analysis of data for 16 patients who completed 4 y of open-label doxazosin treatment showed significant mean reductions in sitting and standing DBP of 7.8 and 9.3 mmHg, respectively (P<0.001 for both reductions) from mean baseline values of 97.0 and 99.4 mmHg, respectively. After 4 y of treatment, sitting and standing mean DBP were reduced to 90 mmHg, the target blood pressure recommended by JNC guidelines.^{26, 27} Mean sitting and standing SBP decreased from 149.6 and 148.3 mmHg, respectively, at baseline to 147.5 and 147.6 mmHg, respectively; these reductions (-2.1 and -0.8 mmHg) were not statistically significant. Among the 178 patients in the original cohort of hypertensive BPH patients, five (2.8%) patients experienced treatment-related postural hypotension compared with two (7.1%) of the 28 patients who completed the study.

Doxazosin GITS in hypertension

The efficacy of doxazosin GITS monotherapy in patients with mild-to-moderate hypertension has been assessed in randomized, double-blind studies.^{20, 30} One study in 392 patients with mild hypertension (SBP 180 mmHg, DBP ranged from 95 to 105 mmHg at randomization) compared doxazosin GITS with doxazosin standard and placebo for 12 weeks.³⁰ A similar study by the same investigators was conducted in 315 patients with mild-to-moderate hypertension (blood pressure 220/95–105 mmHg at randomization) and compared doxazosin GITS with doxazosin standard, also for 12 weeks.²⁰ Patients randomized to doxazosin GITS received an initial dose of 4 mg/day, which could be increased at week 5–8 mg/day, based on patient response to treatment. Patients randomized to doxazosin standard received 1 mg/day initially, titrated to 2 mg/day after 1 week, 4 mg/day at week 3, and 8 mg/day at week 5, as needed to achieve target DBP reduction (sitting DBP of 90 mmHg or a 10 mmHg decrease in baseline DBP). In a combined analysis of the two studies,^{18, 20} similar proportions of patients in the doxazosin GITS (85 and 15%) and doxazosin standard (82 and 17%) groups had mild or moderate hypertension and similar proportions of patients received doxazosin GITS 4 mg/day and doxazosin standard 1–4 mg/day (60 and 61%, respectively). Clinically significant changes in sitting and standing blood pressure were observed in both the doxazosin GITS and doxazosin standard groups, and similar statistically significant decreases were seen in both doxazosin groups relative to placebo. No significant changes in heart rate from baseline were observed among treatment groups. In this combined analysis, doxazosin GITS was as effective as doxazosin standard, and both were more effective than placebo in controlling blood pressure in patients with hypertension.

In a comparison trial, doxazosin GITS was compared with doxazosin standard to determine the effects of the two formulations on blood pressure and lipid metabolism in patients with mild-to-moderate hypertension.³¹ Monotherapy with doxazosin GITS 4 mg and doxazosin standard 4 mg was equally effective in reducing blood pressure in this patient population without altering lipid metabolism. Both formulations produced significant 24-h blood pressure control; however, doxazosin GITS produced a significantly greater reduction than doxazosin standard in night-time systolic and mean ambulatory blood pressure.

Using ambulatory blood pressure monitoring, a recent multicenter study investigated effects of doxazosin GITS on the 24-h blood pressure profile in patients with mild-to-moderate primary hypertension (DBP: 95–115 mmHg).¹⁶ This study demonstrated that a 6-week treatment course with doxazosin GITS (4 mg/day) produced statistically and clinically significant mean reductions in daytime and night-time SBP and DBP that were close to, or consistent with, recommended target levels for ABPM of the German Hypertension League (daytime blood pressure 135/85 mmHg).³² Despite reduction in blood pressure, the physiologic circadian pattern in blood pressure and heart rate was not affected by doxazosin GITS treatment, and the normal 24-h blood pressure profile was preserved. Importantly, this trial demonstrated that a single morning dose of doxazosin GITS 4 mg/day reduced ambulatory SBP and DBP throughout a 24-h period in patients with mild-to-moderate hypertension. In patients with refractory hypertension,³³ doxazosin GITS administered in the morning and evening (4 mg each) produced significantly greater reductions in ambulatory blood pressure (-8.4/-6.1 mmHg, P=0.004) than a single dose of 8 mg, and the reductions were similar for diurnal and nocturnal mean blood pressure. These benefits were manifest in patients receiving an average of three antihypertensive drugs, including doxazosin GITS.

Two recent postmarketing, open-label studies evaluated the safety and effectiveness of replacing the standard formulation of doxazosin with doxazosin GITS in hypertensive patients who were either uncontrolled or recently diagnosed.^{17, 19} Patients tolerating the standard formulation also tolerated the switch to doxazosin GITS, and both formulations were similarly effective and safe.

Effects on blood pressure in normotensive patients with BPH

Studies that examined the effect of doxazosin therapy on blood pressure in normotensive patients with BPH observed no clinically important changes in blood pressure during doxazosin therapy.^{24, 34} A prospective, multicenter, double-blind, placebo-controlled study of 100 normotensive patients (sitting DBP <90 mmHg; mean age 62 y) found that 14 weeks of doxazosin therapy (dose titration for 8 weeks, then stable doses for 6 weeks) was associated with mean decreases from baseline in sitting SBP/DBP of -5.6/-4.1 mmHg and in standing SBP/DBP of -6.0/-4.5 mmHg.³⁵ The reductions from baseline in mean sitting SBP/DBP observed in this study were similar to the mean reductions from baseline reported by Kirby²⁴ in normotensive patients (-5/-4 mmHg) treated with doxazosin. These changes were considered clinically unimportant. Mean changes in sitting and standing SBP/DBP following placebo therapy were +0.7/-0.4 and +1.9/-0.4 mmHg, respectively (P<0.05 for all doxazosin vs placebo comparisons). Heart rate was not significantly changed during doxazosin therapy compared with placebo. The final mean dose of doxazosin was not reported; however, 36 of the 50 (72%) evaluable doxazosin-treated patients received a daily dosage of 8 mg/day. As in other studies of doxazosin standard involving normotensive patients with BPH, the incidence of most commonly reported adverse events was 24% for dizziness, 12% for fatigue, and 12% for headache. In comparison, these adverse events each occurred with an incidence of 4% with placebo. Hypotension occurred in 8% of doxazosin-treated patients vs 0% of placebo-treated patients.

The analyzed pooled safety data from seven completed multicenter, double-blind, placebo-controlled studies of doxazosin treatment in patients with BPH, after stratification by age and blood pressure status,³⁶ included 315 normotensive patients aged <65 y and 320 normotensive patients aged 65 y. Neither of these normotensive age groups showed clinically important reductions in mean blood pressure during treatment with doxazosin. The mean reductions in sitting and standing SBP/DBP were -5/-3 and -3/-3 mmHg, respectively, for patients aged <65 y and -5/-3 and -5/-2 mmHg, respectively, for patients aged 65 y.

Kaplan et al³⁷ have stated that doxazosin therapy has minimal effects on normal blood pressure even if blood pressure is normalized through pharmacologic therapy. The study retrospectively analyzed the 1- and 3-month data from 63 patients (age range, 51–76 y) enrolled in two open-label studies of doxazosin treatment in patients with BPH. The analysis included a comparison of the effects of doxazosin treatment on blood pressure in patients who were either physiologically (n=31) or pharmacologically (n=32) normotensive. At baseline, mean SBP and DBP values in the physiologically normotensive group (134.1 and 81.7 mmHg, respectively) and the pharmacologically normotensive group (134.3 and 81.9 mmHg, respectively) were similar. In all of the pharmacologically normotensive men, hypertension was well controlled by monotherapy with a calcium channel blocker (n=17), an angiotensin-converting enzyme inhibitor (n=6), or a beta blocker (n=9). Patients were given doxazosin at a dosage of 4 mg/day in one study and either 4 or 8 mg/day in the other study.

Statistically significant (P<0.05 vs baseline) but clinically unimportant mean reductions from baseline in SBP and DBP occurred in both the physiologically and pharmacologically normotensive patient groups after 1 and 3 months of doxazosin treatment (Figure 2). There were no statistically significant differences in the mean SBP or DBP changes between the pharmacologically and physiologically normotensive groups, and the effects of doxazosin on SBP or DBP did not increase from 1 to 3 months. Dizziness occurred in a similar proportion of patients in each group: in three of the 31 physiologically normotensive patients and in two of the 32 pharmacologically normotensive patients.

Figure 2.

Changes in SBP and DBP after 1 and 3 months of doxazosin treatment in pharmacologically and physiologically normotensive patients. Data were analyzed at 1 month for 31 pharmacologically normotensive and 28 physiologically normotensive patients and at 3 months for 26 pharmacologically normotensive and 24 physiologically normotensive patients. Reprinted with permission from Kaplan et al.³⁷

Full figure and legend (24K)

Doxazosin GITS in BPH

In trials of doxazosin GITS and doxazosin standard in patients with BPH,^{21, 22} both formulations were shown to significantly improve the symptoms of BPH, as shown by a 45% reduction for each in total IPSS from baseline to final visit, compared with a 34% reduction in patients taking placebo. Doxazosin GITS and doxazosin standard produced comparable improvements in Q_max that were significantly greater than with placebo, with a greater improvement sooner after treatment with doxazosin GITS than with doxazosin standard. Nearly half of the patients taking doxazosin GITS had symptom relief at the 4-mg starting dose. The overall incidence of adverse events was similar among patients treated with doxazosin GITS and placebo, and slightly lower than those taking doxazosin standard. There were no apparent differences in the type of adverse events reported for the two formulations of doxazosin, although most adverse events were reported at a lower frequency with doxazosin GITS.

In a study comparing the effects of doxazosin GITS and the ₁-antagonist tamsulosin in patients with BPH,³⁸ both drugs significantly relieved lower urinary tract symptoms; however, doxazosin GITS produced significantly greater improvements from baseline than tamsulosin in total IPSS (-8.0 vs -6.4) and obstructive IPSS subscore (-5.1 vs -4.0), respectively. Both doxazosin GITS and tamsulosin significantly improved Q_max from baseline; however, the difference between agents did not reach statistical significance (mean change from baseline was 2.6 vs 1.7 ml/s, respectively). Both treatments were well tolerated. In this study, treatment with doxazosin GITS was significantly more effective than tamsulosin in relieving lower urinary tract symptoms.

Comments and conclusions

Sympathetic overactivity can result in excess stimulation of postsynaptic ₁-adrenoceptors in vascular smooth muscle, leading to concentric narrowing of the systemic arterioles, increased peripheral vascular resistance, and elevation of blood pressure.³⁹ In patients with hypertension, doxazosin therapy reduces blood pressure by inhibiting these postsynaptic ₁-adrenoceptors, mediating a reduction in peripheral vascular resistance.^{40, 41}

The precise mechanism underlying the observed minor effects of doxazosin on blood pressure in normotensive patients is unclear. It has been suggested that relative differences in peripheral vascular resistance in these patient subgroups may be a factor³⁷ or that a large drop in SBP/DBP in normotensive patients may be prevented by a compensatory increase in blood pressure secondary to a baroreflex response stimulated by doxazosin-induced hypotension.⁴² Takata et al⁴² suggested that in hypertensive patients, such a reflex increase in blood pressure does not occur because of baroreflex dysfunction. Regardless of the mechanism responsible for the differential effects of doxazosin in hypertensive vs normotensive patients, the fact remains that numerous studies have consistently documented the lack of clinically important changes in blood pressure in normotensive patients receiving doxazosin therapy for BPH.

Findings from clinical studies of normotensive and hypertensive patients with BPH and integrated analyses of such studies indicate that in addition to significantly improving urinary symptoms of BPH, doxazosin treatment, using the GITS or standard formulation, results in clinically important reductions in SBP and DBP in patients with concomitant hypertension but not in patients with normal blood pressure at baseline or in patients with normal blood pressure secondary to other antihypertensive pharmacotherapy.

Doxazosin GITS provides symptomatic relief of BPH and a blood pressure-lowering effect in hypertensive patients that is comparable to that seen with the standard doxazosin formulation. However, because of its improved pharmacokinetic profile, doxazosin GITS can be initiated at a higher dose. Because the goal of BPH treatment is fast relief with minimal adverse events, doxazosin GITS is a reasonable choice of treatment for normotensive or hypertensive patients with BPH.

References

References