Doxazosin Gastrointestinal Therapeutic System: A Clinical Perspective

In this issue of The Journal of Clinical Hypertension there is a study by Dr. Henry Black and colleagues (page 159) concerning the use of α‐blocker therapy as add‐on treatment in hard‐to‐control hypertension. A few comments about the results of this study are in order. Doxazosin is a widely used a‐adrenergic receptor blocker. Its efficacy as monotherapy in lowering blood pressure has been demonstrated, with doses ranging from 1 mg to 16 mg. However, the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) ¹ reported that it does not lower blood pressure as effectively as monotherapy with other agents, nor does it prevent cardiovascular events, in particular congestive heart failure, as effectively as does chlorthalidone. The ALLHAT results have discouraged the use of doxazosin and, by extension, other α blockers as initial monotherapy for hypertension.

The use of doxazosin in combination with other antihypertensive agents is a different story. Many studies have shown that such combinations are highly effective in lowering blood pressure. ² , ³ , ⁴ The study in this issue of the JCH extends such findings to the doxazosin gastrointestinal therapeutic system (GITS) preparation, demonstrating that it is effective when used as add‐on or combination therapy to treat hard‐to‐control or resistant hypertension. It is well‐tolerated and merits wider use in the treatment of resistant hypertension.

The long‐term benefit of doxazosin as an addon drug in preventing cardiovascular events has not been adequately studied or reported. Nevertheless, given the primary importance of blood pressure lowering in preventing events, it is reasonable to conclude that drug combinations that include an α blocker will reduce cardiovascular events if they achieve blood pressure lowering. This is particularly important in patients whose blood pressure is not controlled by combinations using other agents, such as a diuretic or angiotensin‐converting enzyme inhibitor. In addition, the neutral‐to‐positive effects on insulin resistance and lipid profile may add to achieved cardiovascular benefit.

Alpha blockers might be particularly well‐suited when given in combination with a‐β‐blocker because they effectively block the pressor effects of stimulation of the sympathetic nervous system. ⁴ , ⁵ , ⁶ Further, given the atherogenic effects of the sympathetic nervous system, ⁷ combined α/β blockade may confer an important antiatherogenic benefit. Unfortunately, the appropriately sized, long‐term trials are unlikely to be performed. Some information can be gleaned from the Glycemic Effects in Diabetes Mellitus Carvedilol‐Metoprolol Comparison in Hypertensives (GEMINI) study, ⁸ however, in which the α‐β‐blocker carvedilol had fewer adverse metabolic effects than β‐blocker monotherapy with metoprolol. Combined α‐β‐blockade also reduces peripheral resistance, offsetting the increase in peripheral resistance often associated with β‐blocker use. It also reduces blood pressure reactivity to stressful stimuli, an effect that neither β‐blocker monotherapy, α‐blocker monotherapy, or monotherapy with other agents possesses. ⁵

The GITS formulation of doxazosin serves two purposes. First, because of the more gradual absorption of doxazosin, the risk of symptomatic first‐dose effects, such as hypotension, dizziness, and/or syncope is minimized. Second, in the absence of a first‐dose problem, treatment can be initiated at a higher dose, thus reducing the number of titration steps needed.

In studies of doxazosin monotherapy, the dose used has traditionally ranged from 1 mg to 16 mg, with a mean dose between 8 mg and 10 mg. ⁹ However, in several studies of doxazosin as combination or add‐on therapy, the average dose employed and needed is much lower, in the range of only 1 mg to 2 mg. ⁴ , ⁶ , ¹⁰ Clinical experience further suggests that many individuals respond to a dose as low as 0.5 mg. In most cases, there is little to gain by increasing the daily dose above 4 mg daily, or perhaps even 2 mg, when an α blocker is used in combination.

Since blood pressure responds to lower doses when doxazosin is administered as part of combination therapy, it raises the question of whether the 4‐mg GITS formulation might be too high a starting dose for a significant proportion of patients. While the peak plasma concentration following a single 4‐mg dose of doxazosin GITS is roughly the same as the peak plasma level of 1 mg of regular doxazosin, the achieved steady state level would be four times higher. ¹¹ This could increase the risk of dizziness or orthostatic hypotension, particularly when combined with other potent antihypertensive agents. This risk might be higher at times of reduced blood volume in hot weather or reduced oral intake. Thus, initiating α‐blocker treatment at a 4‐mg dose could pose a clinically important problem, not in terms of first‐dose effect, but in terms of steady state drug levels that are higher than needed.

The study by Black et al. provides a hint that this problem might occur. Orthostatic hypotension was reported in six of the 89 subjects who received doxazosin GITS, compared with zero of 86 subjects who received placebo. This 7% incidence rate is considerably higher than the 2% incidence rate reported with regular doxazosin ¹² and is high enough to raise concern. Although the difference between doxazosin and placebo (7% vs. 0) might not have been statistically significant, it nevertheless offers a warning of a clinically relevant increased risk of orthostatic hypotension. This concern should not be dismissed without further studies.

The 4‐mg doxazosin GITS starting dose might be more appropriate when given as monotherapy because of the absence of additive or synergistic effects of the other antihypertensive agents. However, given the low dosage that is usually sufficient when doxazosin is given as add‐on or combination therapy, a 2‐mg formulation of doxazosin GITS would seem likely to be effective and may confer a lower risk of dizziness and orthostatic hypotension. A dose‐response curve largely in the 1‐mg to 4‐mg rather than the 4‐mg to 8‐mg range suggests the wisdom of assessing the efficacy and safety of such a formulation.