Doxazosin Added to Single‐Drug Therapy in Hypertensive Patients with Benign Prostatic Hypertrophy

Abstract

The purpose of this study was to evaluate the efficacy and safety of the addition of doxazosin in the treatment of hypertensive patients who are being treated on another antihypertensive drug.

Methodology. The open‐labelled, noncomparative, multicenter study was carried out in 2363 male hypertensive outpatients >40 years of age, under reasonable control with single antihipertensive drug treatment (diastolic blood pressure <95 mm Hg), and diagnosed with benign prostatic hypertrophy. Doxazosin was started at a dose of 1 mg/day, which was increased at 2‐week intervals to 2 mg/day and 4 mg/day. The study lasted 14 weeks. Blood pressure and heart rate were measured at each of the visits. At baseline and after 14 weeks of treatment, prostatism symptoms were quantified with the International Prostate Symptom Score and quality of life was determined with the American Urology Association Committee Guidelines. Adverse effects were recorded. At the fourth visit, when the patients were taking 4 mg of doxazosin, the blood pressure reduction was 10.7±3/7.1±7.1 mm Hg. The decrease in diastolic blood pressure was significantly more marked in patients treated with β blockers than in patients on calcium antagonists or angiotensin‐converting enzyme inhibitors. For systolic blood pressure, decreases were larger in patients treated with diuretics than with calcium antagonists or angiotensin‐converting enzyme inhibitors. Prostatism symptoms decreased from 15±5.8 points to 7.9±4.3 points (p<0.001) and quality of life improved. Tolerability was good, with only a 4.4% cumulative incidence of adverse effects related to doxazosin. The patients who experienced adverse effects were older and their final blood pressures were lower.

The results of this open‐label study suggest that the addition of doxazosin to another antihypertensive drug in hypertensive patients with benign prostatic hypertrophy is well tolerated and leads to a reduction in prostatic symptoms. The additional beneficial effects on blood pressure suggest that the use of doxazosin may provide a rational approach to this category of patients.

Hypertension is one of the most common chronic diseases in the developed countries. ¹ , ² Benign prostatic hyperplasia (BPH) is one of the most frequent and bothersome health problems in males >50 years of age; more than 50% of males >60 suffer from prostatism. ³ In the United States, treatment of BPH represents approximately 25% of the urologists' total workload. ⁴

According to Beurton, ⁵ microscopic evidence of BPH is present in 100% of males at 80 years of age. The percentage of BPH at autopsy is increasing each year after 40 years of age, ⁶ amounting to >70% after 60 years of age in most studies. ⁷ , ⁸ , ⁹ This phenomenon also extends to clinical symptoms, ¹⁰ although at a lower rate (20% at 60 years; 43% at >80 years). Rates of BPH and symptoms may vary according to regions and culture. In an epidemiologic study carried out in Spain, ¹¹ the prevalence of symptomatic BPH, according to International Prostate Symptom Score (I‐PSS) criteria, was 30% in patients >70 years.

Since both hypertension and BPH are highly common diseases, they are likely to be present simultaneously. Moreover, some reports have suggested an increased incidence of hypertension in subjects with BPH. ¹²

Alpha blockers have been recommended for the treatment of both hypertension and the symptoms caused by BPH. Therefore, it seems attractive to offer this type of treatment to hypertensive patients who present with prostatic symptomology. ¹³ , ¹⁴

Alpha blockers have been recommended in different guidelines for the treatment of hypertension, ¹⁵ , ¹⁶ but not as initial therapy by the Joint National Committee in the U.S. Moreover, α blockers have been advocated for treatment of symptoms of BPH, since blocking prostatic α₁ receptors may improve the dynamic component of flow in patients with BPH.

Treating patients with both hypertension and prostatism with a single drug is logical. One problem that arises is how to treat the prostatism when the blood pressure is controlled with other antihypertensive drugs (pharmacologically normotensive patients). Substituting the antihypertensive drug that the patient is taking with doxazosin, in those cases in which the patient's blood pressure control is good, would seem unethical. However, it has been demonstrated that treatment with doxazosin in normotensive patients can significantly reduce prostatic symptoms without modifying blood pressure. ¹⁷ If doxazosin has favorable effects on BPH and blood pressure in subjects with hypertension, it might be a preferred treatment option for these patients.

We set out to determine the efficacy and safety of the addition of doxazosin to another antihypertensive medication in hypertensive patients with symptomatic BPH. In particular, effects on blood pressure, prostatic symptoms, and quality of life were measured.

MATERIAL AND METHODS

Study Design

An open‐label, noncomparative, multicenter study was conducted. The participants were general practitioners from Spain. The patients were recruited from primary care. The health care authorities were notified of the study and it was carried out in agreement with the pharmacovigilance guidelines in Spain and the ethical guidelines of the Helsinki Declaration.

Patients

The patients included in the study were males >40 years, with hypertension of >1 year's duration that has been controlled (diastolic blood pressure [DBP] ≤95 mm Hg) with a single antihypertensive drug for at least 6 months prior to inclusion and who came to consultation due to symptomatology or prostatic syndrome (I‐PSS questionnaire ≤7 points). Patients with a history of syncope or orthostatic hypotension, dizziness or vertigo, and severe hypertension or prostate cancer were excluded. The degree of control (≤95 mm Hg DBP) would not be considered adequate according to recent guidelines.

Treatment was initiated with 1 mg/day of doxazosin taken orally for the first 2 weeks, titrated at 2‐week intervals to 2 mg/day and 4 mg/day, which is the usual dosage for the treatment of prostatic syndrome. The maximum dosage of 4 mg/day was unchanged throughout 14 weeks of follow‐up unless there were side effects that the patient could not tolerate (postural hypotension, dizziness, or vertigo). In this situation, the dosage of doxazosin or of the other antihypertensive agents was adjusted.

Methods

Blood pressure and heart rate were determined three times at each visit, and the mean of the readings was considered the visit blood pressure. The blood pressure was measured whenever possible by the same individual and using the same arm of the patient, following the recommendations of the British Society of Hypertension.

To quantify the symptoms of the patients, we used the I‐PSS and Quality of Life Assessment developed by the American Urology Association Evaluation Committee, ¹⁸ translated and validated in Spanish, ¹⁹ which the patient filled out during the baseline visit and after 14 weeks of treatment. This questionnaire is made up of seven questions on symptoms, with six possible answers scored from 0–5, which indicate increasing severity of each symptom, so that the minimum score is zero (asymptomatic) and the maximum 35 (very symptomatic). Scores >7 and <19 corresponded to patients with moderate symptoms and scores from 20–35 indicated severe symptoms. Quality of life was scored on the basis of only one question: how the patient would feel if he had to spend the rest of his life with the symptoms he was currently suffering. This question had seven possible answers: from zero (very good) to six (very bad). The score obtained is independent from that of the I‐PSS although the assessment of the quality of life is always used together with the I‐PSS.

All adverse events were recorded, including the date of occurrence, duration, intensity (mild, moderate, severe), seriousness, likelihood of association with the study drug (yes, no, uncertain/unknown), and their resolution.

Statistics

The sample comprised 2363 patients. It was calculated according to the percentage of adverse effects related to the reduction of blood pressure when doxazosin was added to the previous antihypertensive drug at the dosage recommended for the of prostatism or prostatic syndrome.

The side effects produced by blood pressure reduction may differ in both nature and intensity. We used syncope, the most severe adverse effect that can occur with the reduction of blood pressure, to calculate the sample size. The syncope rate in patients treated with any antihypertensive drug has been established as 0.5%–1.0%, with an average value of 0.7% for doxazosin in the clinical trials.

We assumed that a syncope rate greater than twice that documented in the clinical experience (1.4%; odds ratio, 2) after treatment with doxazosin, would be enough to rule out the simultaneous use of doxazosin and another antihypertensive drug in the patients selected for this study.

Descriptive analyses were performed and means with standard deviations and proportions were estimated where appropriate.

Group comparisons were made with analysis of variance. Relations between variables were determined with the Pearson correlation. Two sided p values at 0.05 were taken as statistically significant. Separate analyses were performed for subgroups according to age and initial antihypertensive treatment.

RESULTS

Study population comprised 2363 male patients >40 years of age. Their clinical characteristics of the patients are presented in Table I.

Table I.

Clinical Characteristics of the Patients on Enrollment in the Study

Number of patients	2363
Age	65.4±8.4 years
Mean time of HT diagnosis	6.7±4.7 years
Mean time of BPH evolution	3.5±3 years
Weight	77.1±9.1 kg
Height	1.68±0.1m
Body mass index	27.2±3 kg/m2
Mean blood pressure	150.5±13.2/86.9±6.5 mm Hg
HT=hypertension; BPH=benign prostatic hypertrophy

All patients were treated with a single antihypertensive drug; 1264 (53.4%) were treated with angiotensin‐converting enzyme (ACE) inhibitors, 592 (25.1%) with calcium antagonists, 159 (6.7%) with β blockers, and 344 (14.6%) with diuretics. In all patients, this treatment was maintained without change until the sixth week of the study, when the 4‐mg dosage of doxazosin had been reached.

Table II shows the changes in heart rate and blood pressure from the first to the fifth visit, after 14 weeks of treatment. At the time of the fourth visit, when the patients were taking 4 mg of doxazosin, systolic blood pressure (SBP) was reduced by 10.7±11.3 mm Hg and DBP by 6.1±7.1 mm Hg compared to baseline levels.

Table II.

Evolution of Blood Pressures and Heart Rate

	Visit 1	Visit 2	Visit 3	Visit 4	Visit 5
SBP	150.5±13	146.1±13	143.0±13	140±13	138.6±12
DBP	86.9±6	84.4±7	82.4±7	80.8±7	80.1±7
HR	75.8±8	75.2±8	74.7±7	74.3±7	73.8±8
All of the differences are significant (p<0.001) in regard to first and subsequent visits. SBP=systolic blood pressure in mm Hg; DBP=diastolic blood pressure in mm Hg; HR=heart rate in beats per minute

The mean age was not different between the four treatment groups. When analyses were performed separately for those younger and those older than 65 years of age, no significant differences in blood pressure response to doxazosin were observed.

At the fourth visit, SBP had decreased by 10.6%±11.8% in the older subjects and by 10.7%±10.6% in the younger ones (not significant) and DBP by 6.1%±7.2% and 6.2%±6.9%, respectively (not significant).

Blood pressure responses differed according to the antihypertensive treatment previously administered and maintained by the patients (Fig. ). Both the SBPs and DBPs were similar in all the treatment subgroups at baseline. After combined treatment with doxazosin, both SBP and DBP values decreased in the four treatment groups, and the decrease was more pronounced for the patients being treated with β blockers, although not statistically significant.

Figure.

Evolution of blood pressure based on type of antihypertensive drug with which the patients were treated previously. *p<0.001 For monotherapy vs. combination therapy with doxazosin DBP=diastolic blood pressure; SBP=systolic blood pressure; B=Baseline: patients with previous antihypertensive drug; F=Final: patients with previous antihypertensive drug+doxazosin; ACEi=angiotensin‐converting enzyme inhibitor; CCB=calcium channel blocker; BB=β blocker; D=diuretic

The percentage of decrease in DBP, calculated as the third visit compared to the baseline visit, was statistically significantly larger for the group treated with β blockers than the groups treated with calcium antagonists and ACE inhibitors (p<0.05). The differences in decreases of SBP were not significant.

The decrease in SBP between baseline and the fourth visit was larger in patients treated with diuretics than those on calcium antagonists or ACE inhibitors (p<0.05). The decreases in DBP did not differ significantly between the different treatment groups (Table III).

Table III.

Percentage of Decrease in Blood Pressure Relative to Other Antihypertensive Treatment

Percentage Decrease when Doxazosin Is Added to:	ACE Inhibitor	Calcium Antagonist	β Blocker	Diuretic
SBP B‐3	7.3±9.2	7.2±9.7	8.3±9.5	8.4±9.9
DBP B‐3	4.4±5.9	4.3±6.2	5.4±5.9*	4.5±6.6
SBP B‐4	10.3±11.0	10.2±11.5	11.6±11.3	12.3±12.0**
DBP B‐4	5.9±7.1	5.9±6.8	7.0±7.0	6.9±7.4
*p<0.05: β Blocker compared to ACE inhibitor and calcium antagonist; **p<0.05: diuretic compared to ACE inhibitor and calcium antagonist ACE=angiotensin‐converting enzyme; SBP B‐3=Percentage decrease in systolic pressure on visit three compared to baseline; DBP B‐3=the same for diastolic pressure; SBP B‐4 and DBP B‐4=the same for visit four

The prostate symptomatology score decreased with the addition of doxazosin to the antihypertensive treatment, from 15±5.8 points at the baseline visit to 7.9±4.3 points (p<0.001) at the final visit.

The overall decrease in the I‐PSS percentage between the baseline and the final visit (14 weeks) was 46.6%±21.5 %. Prostatic symptoms worsened in only 12 patients. The percentage decrease was larger (49.2±21) in the most severely affected patients (I‐PSS >20 points at the baseline visit), than in the less symptomatic patients (I‐PSS <20 points), in whom the percentage decrease was 46.1±21.5 (p<0.05). The correlation between the initial score of the I‐PSS and the percentage decrease obtained during the treatment was significant (p<0.05; r=0.12). The prostate symptoms improved to the same extent in all four groups.

Of the patients, 44.8% completed the protocol with an I‐PSS score <7 points; 26 of these patients had a zero score. Of the 28 patients (1.2%) who began the treatment with the highest score, only one of them remained in this category. The percentage decrease was less in the older subjects (48.6%±21.8% in those <65 years compared to 45%±21.1% in those >65 years; p<0.001). In addition, quality of life improved after treatment (baseline score 4.3±1.1 and 2±1.1 post‐treatment; p<0.001).

Safety and Tolerability

Among the 2363 participants, 272 adverse events occurred in 231 patients (9.7%). Adverse effects that were considered to have a causal relationship with doxazosin occurred in 104 patients (4.4%). They were: dizziness in 65 (2.7%), vertigo in 10 (0.4%), hypotension in 20 (0.8%), and syncope in nine (0.3%) patients.

Patients experiencing doxazosin‐related side effects were significantly older (67.4 vs. 65.4 years; p<0.05). Weight, height, body mass index, blood pressures, heart rate, I‐PSS questionnaires, and baseline quality of life did not differ statistically. However both the SBP and the DBP at the fourth visit were lower in the group reporting doxazosin related side effects (134.2±16.8/77.7±10.1 mm Hg vs. 139.9±12.9/80.8±6.8/80.8±7.3 mm Hg; p<0.05).

DISCUSSION

This study shows that adding doxazosin to the treatment of hypertensive patients with BPH who have been receiving antihypertensive single‐drug treatment significantly reduces the prostatic symptomatology.

The absence of significant blood pressure reduction in patients with controlled blood pressure has been documented in other studies performed in normotensive patients with BPH. ²⁰ , ²¹ According to the authors, it seems that doxazosin would exert its antihypertensive effect only when peripheral vascular resistance is increased. ²² , ²³ Other European studies ²⁴ , ²⁵ have demonstrated that the blood pressure reductions obtained with doxazosin in normotensive patients do not differ from those obtained with a placebo.

This has also been confirmed by a study performed by Pickering et al. ²⁶ in which 24‐hour arterial blood pressure measurement was used. The study was carried out in 112 chronic hypertensive patients, 23 of whom had “white coat” hypertension patients. In the chronic hypertensive patients, the 24‐hour mean blood pressure was reduced by 10/8 mm Hg with doxazosin and in the white coat hypertensives, the mean reduction was 0.5/2 mm Hg. This suggests that doxazosin has a small effect on the blood pressure of normotensive individuals.

The side effects manifested by our patients were generally mild, except for syncope, which coincides with the studies previously reported. ²⁷

As has been demonstrated by other authors, ²⁸ there were no differences in terms of the type of adverse effects and the antihypertensive drugs used before the introduction of doxazosin. In our study, we found a larger antihypertensive effect when doxazosin was combined with a diuretic or β blocker than when it was added to an ACE inhibitor or calcium antagonist. Side effects tended to occur early after onset of treatment with doxazosin. The differences in blood pressures with the different doxazosin combinations were larger after the patient had remained in treatment for at least 2 months, at a dosage of 2 mg/day or 4 mg/day, but not after 1 month at 1 mg/day. Therefore, it appears that side effects of the drug mainly result from the first dosage. This effect may be reduced when the new sustained release formulation of doxazosin is available. ²⁹ , ³⁰

We used the I‐PSS and the quality of life assessment developed by the Assessment Committee of the American Urology Association, ¹⁸ adapted to and validated in Spanish, ¹⁹ to quantify the prostatism symptoms, taking their limitations into consideration. Notably, symptoms generally defined as “prostatism” can sometimes exist in the absence of prostate enlargement. Such diseases as benign prostatic obstruction, which occur in cases of vesical neck sclerosis or detrusor muscle with low contractile activity, have a low incidence and do not improve with α blocker treatment.

Given the size of our study (2363 patients) and the setting in which it was carried out (primary health care), it was not feasible to carry out complementary assessments of prostatic volume, flowmeter, endovesical/micturition flow pressure ratio, or postmicturition residual volume, which would have provided a better diagnosis. A major limitation of this study is that it was an open‐label trial. A placebo effect and more careful follow‐up of patients may have accounted for some of the blood pressure results and improvement in symptoms. Nevertheless, the study suggests that the use of doxazosin in patients with hypertension and BPH who are being treated with other antihypertensive drugs may reduce symptoms of BPH and have additional blood pressure‐reducing effects with relatively few side effects.

Acknowledgments: This study has been carried out under the sponsorship of Pfizer, SA. We thank all of the primary health care physicians who participated in this study for their valuable collaboration.