What is the role of doxazosin in the treatment of hypertension (HTN)?

Role of Doxazosin in Hypertension Treatment

Doxazosin should not be used as a first-line agent for hypertension and should be reserved only for cases where other antihypertensive medications at maximum tolerated doses have failed to achieve blood pressure control. 1

Mechanism and Indication

• Doxazosin is an alpha-1 adrenergic receptor blocker that lowers blood pressure by causing selective blockade of the alpha-1 (postjunctional) subtype of adrenergic receptors, resulting in decreased systemic vascular resistance 2
• While FDA-approved for the treatment of hypertension (either alone or in combination with other antihypertensive agents), evidence from clinical trials has significantly limited its recommended use 2, 1

Evidence Against First-Line Use

• In the ALLHAT trial (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial), doxazosin was found to be inferior to chlorthalidone for the prevention of heart failure and was associated with doubling the risk of heart failure compared to chlorthalidone 1
• The doxazosin arm of ALLHAT was stopped prematurely after a 3.3-year median follow-up due to these concerning findings 1
• The 2017 ACC/AHA guidelines note that chlorthalidone reduced the risk of heart failure with reduced ejection fraction (HFrEF) more than doxazosin 1
• Alpha-blockers such as doxazosin are associated with increased incidence of adverse events including heart failure, renal complications, hyperkalaemia, and hypotension 1

Current Guideline Recommendations

• The American Heart Association specifically states that alpha-adrenergic blockers such as doxazosin should be avoided and might be used only if other drugs for the management of hypertension and heart failure are inadequate to achieve blood pressure control at maximum tolerated doses 1
• Doxazosin is classified as "III: Harm" with Level of Evidence C in patients with structural cardiac abnormalities, indicating potential harm 1
• The 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APA/ASH/ASPC/NMA/PCNA guideline for hypertension management does not recommend alpha-blockers as first-line therapy 1

Specific Clinical Scenarios

• Patients with heart failure: Doxazosin should be particularly avoided in patients with heart failure or at risk for heart failure 1
• Patients with BPH and hypertension: Doxazosin may have a role in treating men with concurrent benign prostatic hyperplasia (BPH) and hypertension, as it can improve urinary symptoms while controlling blood pressure 3, 4
• Elderly patients: While doxazosin has been studied in elderly patients with hypertension, its increased risk of orthostatic hypotension makes it less desirable in this population compared to other agents 5
• Patients with obesity: Doxazosin has been associated with weight gain, likely due to extracellular fluid volume expansion, making it less suitable for patients with weight concerns 1

Appropriate Use Scenarios

• As add-on therapy when blood pressure remains uncontrolled despite maximum tolerated doses of first-line agents (thiazide diuretics, ACE inhibitors, ARBs, and calcium channel blockers) 6
• In men with concurrent BPH and hypertension who have not responded adequately to other antihypertensive medications 3, 4

Dosing and Administration

• Doxazosin is available in standard and extended-release gastrointestinal therapeutic system (GITS) formulations 7
• The GITS formulation may have advantages over standard doxazosin in terms of simpler dosing regimen and improved tolerability 7
• Careful dose titration is required to minimize first-dose hypotension, particularly with the standard formulation 7

Common Pitfalls and Caveats

• First-dose phenomenon: Patients may experience significant hypotension with the first dose, particularly when standing, requiring careful dose titration 2
• Orthostatic hypotension: Doxazosin has a greater effect on blood pressure and heart rate in the standing position, increasing fall risk 2
• Heart failure risk: Vigilance for signs and symptoms of heart failure is necessary when using doxazosin 1
• Drug interactions: Consider potential interactions with other medications that lower blood pressure, including PDE-5 inhibitors 2

In summary, doxazosin should be considered a last-line agent for hypertension treatment, reserved for cases where other antihypertensive medications have failed to achieve adequate blood pressure control or in specific situations such as concurrent BPH and hypertension.