Controlled‐Release Doxazosin as Combination Therapy in Hypertension: The GATES Study

Abstract

Doxazosin gastrointestinal therapeutic system (GITS) or placebo was added to the antihypertensive therapy of uncontrolled hypertensive patients in a prospective, randomized, double‐blind trial. Patients received doxazosin GITS 4 mg/d (n=89) or placebo (n=86) for 6 weeks in addition to entry antihypertensive medication. Doxazosin GITS was increased to 8 mg/d after 2 or 4 weeks if patients did not respond (sitting blood pressure <140/90 mm Hg and 10/10‐mm Hg decrease from baseline). Reductions from baseline in sitting and standing blood pressures were greater with doxazosin GITS than placebo at all time points (p≤0.017) except Week 1 sitting systolic pressure (p=0.068). The response rate was greater in the doxazosin GITS group (37.3%) than the placebo group (10.7%; p<0.001). With the exception of postural hypotension (7% compared with 0.0%), the frequency of adverse events was similar for doxazosin GITS and placebo. Doxazosin GITS was effective as combination antihypertensive therapy with the major classes of antihypertensive agents.

Although hypertension affects nearly one billion people worldwide, ¹ only 70% of those with hypertension are aware of their high blood pressure (BP), ² and only 59% receive antihypertensive treatment. ² Untreated hypertension causes stroke, myocardial infarction, cardiac failure, dementia, and renal failure. ¹ Despite major efforts to diagnose and treat hypertension, the recommended goal BP of <140/90 mm Hg is often not achieved. ³

Current guidelines recommend various antihypertensive agents, including thiazide‐type diuretics for most patients and angiotensin‐converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), and β blockers (BBs) as initial treatment for specific indications in hypertensive patients. ² Because monotherapy is often not sufficient, the guidelines suggest combination therapy to achieve BP goals. ² Real‐world data on the effectiveness of BP lowering with specific antihypertensive agents when used in combination therapy are, however, lacking.

Doxazosin, an α₁‐adrenoreceptor antagonist, ⁴ has been shown to be effective for the treatment of hypertension when used in combination with other agents. ⁵ , ⁶ Doxazosin gastrointestinal therapeutic system (GITS) ⁷ has an enhanced pharmacokinetic profile compared with the standard immediate‐release formulation. The GITS formulation simplifies dosing by eliminating multiple dose titrations and allowing a therapeutic dose of doxazosin to be administered at initiation of therapy. Doxazosin GITS formulation has been demonstrated to be effective and well tolerated as monotherapy in clinical trials for treatment of hypertension and benign prostatic hyperplasia. ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³

The primary objective of the Doxazosin GITS as Combination Therapy for Hypertensive Subjects: An Efficacy and Safety (GATES) study was to evaluate the efficacy of doxazosin GITS when used as add‐on therapy in patients with inadequately controlled primary (essential) hypertension who are already being treated with no more than two antihypertensive medications from the five major classes of antihypertensive agents: ACEIs, ARBs, CCBs, BBs, and diuretics. The secondary objectives were to determine the safety and lipid effects of doxazosin GITS when used in combination therapy.

Study Design

The GATES study was a prospective, randomized, double‐blind, placebo‐controlled trial performed in 16 centers in Europe and one center in the United States. The study was divided into two phases. The first phase (phase I) consisted of a placebo run‐in lasting 2 weeks. Patients meeting inclusion criteria were treated daily with single‐blind placebo plus their entry antihypertensive medications. Patients were monitored at the beginning (Week ‐2) and end (Week 0) of the run‐in period, and baseline BP and lipid measurements were collected at the end of the run‐in period (Week 0). Phase II was an efficacy phase lasting 6 weeks. Patients qualifying for the study after the run‐in period were randomized to receive doxazosin GITS or matching placebo in addition to their entry antihypertensive medication. The study protocol was approved by the ethics committee at each center and was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent.

Entry Criteria

Patients were recruited into the study if they were aged 18 years or older and had primary (essential) hypertension not controlled by current medication. Hypertension was defined as sitting diastolic BP (DBP) ≥90 and ≤105 mm Hg and sitting systolic BP (SBP) ≥140 and ≤160 mm Hg. BP was measured as the average of three readings at each of two consecutive visits. Patients could be taking no more than two individual antihypertensive agents of the following classes prescribed solely for BP control at accepted effective or maximum tolerated dose for at least 2 weeks before study entry: CCB, ACEI, ARB, BB, or diuretic.

Exclusion Criteria

Patients were excluded from the study if their entry antihypertensive therapy was not at accepted effective doses or at the maximum dose tolerated by the patients or if patients were taking more than two antihypertensive agents at entry or medications not listed in the inclusion criteria. Other exclusion criteria included angina pectoris; acute myocardial infarction; stroke within 6 months of study entry; known congestive heart failure; hypertensive retinopathy of grade 3 or higher; orthostatic hypotension as defined by a decrease of ≥20 mm Hg in SBP or 10 mm Hg in DBP between sitting and standing after 30 seconds; known fluid depletion; secondary hypertension; pregnancy or not practicing contraception (if female); hepatic or renal dysfunction; poorly controlled diabetes (glycosylated hemoglobin [HbA_lc] >10%); history of drug or alcohol abuse; significant gastrointestinal (GI) stricture or GI disease; a sensitivity to doxazosin or α₁‐adrenoreceptor antagonists, or quinazolines; concomitant treatment with other potentially vasoactive medications; and blood donation during or within 2 weeks after completion of the study.

Treatments

During the placebo run‐in period (phase I), patients received placebo in addition to entry antihypertensive medications. During the efficacy period (phase II), patients were randomized to receive one tablet of doxazosin GITS 4 mg or matching placebo per day in addition to their entry antihypertensive medication. Medication was taken orally each morning, including the morning of a clinic visit. Dose titration (two doxazosin GITS 4‐mg tablets [equal to GITS 8 mg] or matching placebo) was required if, at the end of Weeks 2 and/or 4, average SBP and DBP were ≥140/≥90 mm Hg and there was a ≤10‐mm Hg decrease from baseline in both SBP and DBP.

Patients not in compliance with study or entry medications (>20% deviation) for two consecutive visits were withdrawn from the study.

Efficacy Measures

The primary efficacy variable was the change from baseline in sitting DBP. Secondary efficacy variables were sitting SBP, standing SBP and DBP, standing and sitting heart rate, change from baseline in fasting lipid profile, change from baseline in HbA_lc, and the proportion of patients responding to medication. Response to medication was defined as mean sitting SBP and DBP values of <140 mm Hg and <90 mm Hg, respectively, in addition to a ≥10/10‐mm Hg reduction in BP from baseline.

Efficacy variables and compliance with study medication and entry antihypertensive medications were assessed at the end of Weeks 1, 2, 4, and 6. Fasting lipid profile and HbA_lc were measured before and after the trial.

Safety Assessments

All adverse events (AEs) as reported by the patient or observed by the investigator, including clinically significant changes in physical examination findings, were recorded on the case report form. Routine clinical laboratory tests were performed for hematology, biochemistry, lipids, urinalysis, and pregnancy. Abnormal test results were recorded as AEs if they resulted in a change in study medication dosage or discontinuation or if they required intervention to assess the risk to the patient.

Statistical Analyses

A sample size of 75 patients per treatment group was needed to detect a difference between treatment groups in mean change from baseline in sitting DBP of 4 mm Hg with 80% statistical power using a two‐sided 95% confidence interval, assuming an SD of 8.6 mm Hg for the change from baseline in sitting DBP.

Data are reported as mean ± SD, unless otherwise specified. All analyses were conducted on the intent‐to‐treat population, which included patients taking at least one dose of the active study medication and having baseline and at least one postbaseline measurement. Hypothesis testing was carried out at a 5% level of significance (p≤0.05). If a patient discontinued, then the last observation carried forward (LOCF) was used for end point analysis. Baseline comparisons were made using two‐way analysis of variance with effects for treatment group and country for continuous variables. Postbaseline assessments were carried out at each visit and at the final visit. Treatment comparisons were performed using two‐way analysis of covariance with effects for treatment group, country, and baseline (as covariate) for continuous variables. Within‐treatment comparisons (change from baseline) were performed using a paired t test. The Cochran‐Mantel‐Haenszel test stratified by country was used to compare the two treatment groups for categoric variables.

Patients

A total of 272 patients were screened, and 175 patients were randomized to receive doxazosin GITS (n=89) or placebo (n=86). There were no significant differences between treatment groups in baseline characteristics, as shown in Table I. Eight patients withdrew from the trial prematurely: six patients treated with doxazosin GITS (6.7%) withdrew (five patients due to an AE and one patient failed to attend one visit), and two placebo‐treated patients (2.3%) withdrew due to an AE. A total of 167 patients completed the study. Entry antihypertensive medications are shown in Table II.

Table I.

Baseline Characteristics of the Intent‐to‐Treat Population

		Doxazosin GITS			Placebo
	Men	Women	Total	Men	Women	Total
No. of patients	54	35	89	52	34	86
Age (yr)	57.7±9.6	51.9±10.7	55.4±10.4	52.2±9.9	55.0±9.3	53.3±9.7
Race
White	49 (90.7)	32 (91.4)	81 (91.0)	49 (94.2)	29 (85.3)	78 (90.7)
Black	5 (9.3)	3 (8.6)	8 (9.0)	3 (5.8)	5 (14.7)	8 (9.3)
Weight (kg)	88.4±14.7	76.8±13.0	–	87.5±10.2	77.9±14.0	–
Height (cm)	174.9±7.9	162.6±7.4	–	175.6±6.1	162.6±6.0	–
Data are presented as mean ± SD or n (%). GITS=gastrointestinal therapeutic system

Table II.

Entry Antihypertensive Medications*

	Doxazosin GITS (n=89)		Placebo (n=86)
Prevalence/Medication Type	n	%	n	%
Patients who took at least one antihypertensive concomitant medication	89	100.0	85	98.8
Angiotensin‐converting enzyme inhibitors	41	46.1	42	49.4
Angiotensin II receptor blockers	14	15.7	14	16.5
Calcium channel blockers	26	29.2	16	18.8
β Blockers	36	40.4	26	30.2
Diuretics	19	21.3	25	29.4
GITS=gastrointestinal therapeutic system; *at study entry, patients could take no more than two antihypertensive medications and were taking an average of 1.5

Efficacy

Of the patients receiving doxazosin GITS, 65.2% were titrated to a dosage of 8 mg/d at the end of Week 2, and remained on this dosage until the end of the trial. At the study end point, 30.3% were receiving 4 mg/d and 67.4% required 8 mg/d.

Combination therapy with doxazosin GITS was significantly more effective in reducing BP than was combination therapy with placebo. Reductions in sitting DBP were significantly greater in the doxazosin GITS group than in the placebo group at all time points (Figure 1A). Reductions in sitting SBP were significantly greater in the doxazosin GITS group than in the placebo group at all time points except Week 1 (Figure 1B).

Figure 1.

Sitting blood pressure (BP). A) Change from baseline in diastolic BP (least squares [LS] mean ± standard error [SE]). B) Change from baseline in systolic BP (LS mean ± SE). Baseline sitting diastolic BP (mean ± SD) was 96.7±4.2 mm Hg in the doxazosin GITS group and 97.3±4.7 mm Hg in the placebo group. Baseline sitting systolic BP (mean ± SD) was 149.7±6.6 mm Hg in the doxazosin GITS group and 150.9±6.5 mm Hg in the placebo group. LOCF=last observation carried forward; DOX=doxazosin; GITS=gastrointestinal therapeutic system

Reductions in standing BP measurements also were significantly greater in the doxazosin GITS group than in the placebo groups at all time points (p≤0.01 for DBP and p≤0.017 for SBP). Baseline standing DBP was 96.1±6.0 mm Hg in the doxazosin GITS group and 97.5±5.6 mm Hg in the placebo group. Doxazosin GITS reduced standing DBP −9.6±1.3 vs. −2.5±1.3 mm Hg in the placebo group (at LOCF least squares [LS] mean ± standard error [SE], p<0.001 vs. placebo). Baseline standing SBP was 147.0±9.4 mm Hg in the doxazosin GITS group and 148.9±8.8 mm Hg in the placebo group, and doxazosin GITS reduced standing SBP −12.7±2.1 vs. −4.2±2.0 mm Hg in the placebo group (LOCF LS mean ± SE, p<0.001 vs. placebo; Table III).

Table III.

Change From Baseline to LOCF End Point in Standing Blood Pressure (BP) and Standing and Sitting Heart Rate

	Doxazosin GITS Δ (n)	PlaceboΔ (n)
Standing diastolic BP (mm Hg)	−9.6±1.3*† (89)	−2.5±1.3† (86)
Standing systolic BP (mm Hg)	−12.7±2.1*† (89)	−4.2±2.0† (86)
Sitting heart rate (bpm)	−0.8±1.5† (89)	−1.7±1.5† (85)
Standing heart rate (bpm)	1.8±1.6 (89)	−1.0±1.7† (85)
Data are presented as least squares mean ± standard error. LOCF=last observation carried forward; GITS=gastrointestinal therapeutic system; Δ=change; *p<0.001 between groups; † p=0.05 vs. baseline

The proportion of patients whose BP was reduced to <140/90 mm Hg in addition to a 10/10‐mm Hg reduction in BP (responders) was significantly greater with doxazosin GITS compared with placebo (Figure 2). The proportion of responders was statistically significantly greater in the doxazosin GITS group at all time points (p<0.03). In addition, at Week 6, the proportion of patients achieving goal BP recommended by current guidelines (<140/90 mm Hg) was significantly greater in the doxazosin GITS 4‐mg/d group than in the placebo group (49.4% vs. 14.3%; p<0.001).

Figure 2.

Proportion of patients responding to treatment with blood pressure (BP) <140/90 mm Hg in addition to ≥10/10‐mm Hg decrease in BP from baseline. DOX=doxazosin; GITS=gastrointestinal therapeutic system; LOCF=last observation carried forward

Although sitting heart rate was significantly decreased from baseline in both groups at LOCF end point (LS mean ± SE, doxazosin GITS, −0.8±1.5 bpm; placebo, −1.7±1.5 bpm; p≤0.05 vs. baseline for both), there were no statistically significant differences between groups (p≥0.50; Table III).

No statistically significant differences between treatment groups were observed in total cholesterol, triglycerides, low‐density lipoprotein cholesterol, high‐density lipoprotein (HDL) cholesterol, or HDL/total cholesterol ratio at baseline or change from baseline at LOCF end point. No statistically significant differences between treatment groups in mean HbA_lc concentrations at baseline or in the change from baseline at LOCF were noted (data not shown).

Safety and Tolerability

No deaths occurred during the study in either treatment group. One treatment‐related severe AE was seen in each group: one doxazosin GITS‐treated patient experienced severe treatment‐related epi‐staxis, and one placebo‐treated patient experienced severe treatment‐related asthenia. Sixty‐five treatment‐related AEs were experienced by 46 patients. Treatment‐related AEs were noted in 24 patients in the doxazosin GITS group and 22 patients in the placebo group. The most frequently reported AEs were dizziness, headache, asthenia, and postural hypotension (decrease of ≥20 mm Hg in SBP or 10 mm Hg in DBP between sitting and standing after 30 seconds), with postural hypertension noted in the doxazosin GITS group only (Table IV). The five patients in the doxazosin group who withdrew because of an AE withdrew for the following reasons: three patients with orthostatic hypotension; one patient with dizziness, and one patient with dizziness and nausea.

Table IV.

Treatment‐Emergent, Treatment‐Related Adverse Events (AEs)

	Doxazosin GITS (n=89)		Placebo (n=86)
	n	%	n	%
Prevalence
AEs	39	–	26	–
Patients with AEs	24	27.0	22	25.6
Patients with severe AEs	1	1.1	1	1.2
Patients who discontinued because of AEs	5	5.6	2	2.3
Nature of AEs
Dizziness	6	6.7	5	5.8
Postural hypotension	6	6.7	0	–
Asthenia	1	1.1	4	4.7
Headaches	2	2.2	2	2.3
Abdominal pain	1	1.1	3	3.5
Dyspepsia	1	1.1	2	2.3
Palpitation	2	2.2	0	–
Paresthesia	2	2.2	0	–
Somnolence	2	2.2	0	–
All AEs shown were treatment‐emergent and treatmentrelated. GITS=gastrointestinal therapeutic system

DISCUSSION

The GATES study demonstrated that in patients whose hypertension was previously uncontrolled by antihypertensive medication, combination therapy with doxazosin GITS significantly reduced both DBP and SBP compared with placebo at all time points except for sitting SBP at Week 1. The response to treatment, defined for this study as mean sitting SBP and DBP values of <140 mm Hg and <90 mm Hg in addition to a ≥10/10‐mm Hg reduction from baseline, was significantly greater in the doxazosin GITS group (37.3%) than the placebo group (10.7%; p<0.001). In addition, the percentage of patients achieving goal BP (<140/90 mm Hg) as recommended by current guidelines ² , ¹⁴ was significantly greater for those taking doxazosin GITS (49.4%) compared with those taking placebo (14.3%; p<0.001). No statistically significant changes from baseline in lipids or HbA_1c were observed in either group, and treatment with GITS was generally well tolerated. There were no significant differences between treatment groups in the total number of AEs or the number of patients experiencing AEs.

Other large clinical trials during which BP was aggressively managed have suggested that patients already receiving antihypertensive therapy may achieve additional BP‐lowering benefit from adding another antihypertensive agent to their current regimen. ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ After 5 years of treatment in the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT; n=33,357), goal BP (SBP <140 mm Hg and DBP <90 mm Hg) was obtained in only 65% of patients, despite a mean of two medications per patient. ¹⁵ The ALLHAT trial was designed to determine whether amlodipine, lisinopril, or doxazosin monotherapy would reduce the incidence of fatal coronary heart disease and nonfatal myocardial infarction compared with chlorthalidone. In ALLHAT, the doxazosin arm was discontinued early because of an increased rate of combined cardiovascular disease, stroke, and heart failure. ¹⁶ ALLHAT clearly demonstrated that mono‐therapy with doxazosin as initial therapy was not as effective as traditional therapy with chlorthalidone. Patients in the Hypertension Optimal Treatment (HOT) trial ¹⁷ (n=18,790), designed to evaluate the effects of intensive BP reduction on the incidence of cardiovascular complications in patients with hypertension, required treatment with up to three different antihypertensive drugs (felodipine, ACEI or BB, and diuretic) to reduce their DBP to one of three DBP targets ≤90 mm Hg.

Consistent with our findings that doxazosin GITS provides additional BP‐lowering benefit when added to the combination therapy of patients with uncontrolled hypertension, Black et al. ⁵ demonstrated that doxazosin (in the standard formulation) as add‐on therapy improved BP control in patients previously uncontrolled on monotherapy with a CCB, ACEI, BB, or diuretic, with tolerability not different from placebo. In addition, a statistically significant improvement in the plasma lipid profile in the doxazosin standard group was observed.

Other trials assessing the effectiveness of doxazosin in combination therapy for treating hypertension resistant to monotherapy have involved small numbers of patients for short periods of time. In these studies, doxazosin was combined with nifedipine, amlodipine, BBs, ACEIs, and diuretics, with overall positive results. ⁴ GATES complements the recently concluded Anglo‐Scandinavian Cardiac Outcomes Trial (ASCOT), ²⁰ , ²¹ in which doxazosin GITS was being used as add‐on therapy (step 5) in combination with amlodipine and perindopril or atenolol and bendroflumethiazide to determine the effects of BP lowering on fatal and nonfatal coronary outcomes. More than 40% of the volunteers in this study were receiving doxazosin GITS in addition to their two‐drug therapy at Year 3 (Neil Poulter, MBBS, MSc, FRCP [an ASCOT investigator], written communication, June 2005).

In the present study, doxazosin was well tolerated when added to patients' previous antihypertensive treatment regimen at a therapeutic dose without subtherapeutic dose titration. In other trials comparing the tolerability of doxazosin GITS 4 mg with doxazosin standard, administered at a subtherapeutic dose and titrated over several weeks to 4 mg, both formulations were equally well tolerated. ²² , ²³

CONCLUSIONS

The GATES trial demonstrated the incremental benefits of controuedrelease doxazosin GITS compared with placebo in reducing BP in patients who were hypertensive at baseline despite antihypertensive therapy with no more than two baseline antihypertensives from the five major antihypertensive drug classes. Clinically and statistically significant reductions in SBP and DBP were observed over the 6‐week treatment period in patients with doxazosin GITS added to their entry medication compared with the BP response in patients with placebo added to their entry medication(s). Doxazosin GITS did not adversely affect lipids or HbA_lc, and doxazosin GITS was well tolerated. These data support the role of α₁‐adrenoreceptor antagonists as add‐on therapy to what is currently recommended as initial and even second‐step treatment.

Disclosure: This study was funded by Pfizer Inc.