Management of Uncontrolled Hypertension on Triple Therapy
Add spironolactone 25 mg daily as the fourth agent to this patient's current regimen of chlorthalidone, amlodipine, and carvedilol. 1
Current Regimen Assessment
This patient meets the definition of resistant hypertension, being uncontrolled on three antihypertensive agents including a thiazide-like diuretic at appropriate doses. 2 The current regimen includes:
- Chlorthalidone 25 mg - already at the optimal dose for resistant hypertension, which provides superior 24-hour blood pressure reduction compared to hydrochlorothiazide 2
- Amlodipine 10 mg - at maximum dose
- Carvedilol 12.5 mg BID - a vasodilating beta-blocker with favorable metabolic effects compared to traditional beta-blockers 2
The combination of a thiazide-like diuretic, calcium channel blocker, and beta-blocker represents a reasonable foundation, though the ideal triple therapy typically includes an ACE inhibitor or ARB instead of a beta-blocker. 2
Primary Recommendation: Add Spironolactone
Add spironolactone 25 mg daily as the fourth agent. 1 This mineralocorticoid receptor antagonist provides an average additional blood pressure reduction of 25 mmHg systolic and 12 mmHg diastolic when added to existing multidrug regimens. 1 Recent studies demonstrate significant antihypertensive benefit of aldosterone antagonists in patients uncontrolled on multidrug regimens. 2
Alternative Fourth Agents if Spironolactone Not Tolerated
- Eplerenone - selective mineralocorticoid receptor antagonist with lower risk of gynecomastia 3
- Amiloride - potassium-sparing diuretic alternative 3
Consider Replacing Carvedilol with ACE Inhibitor or ARB
The more evidence-based triple regimen consists of an ACE inhibitor or ARB, calcium channel blocker, and thiazide diuretic, which is effective and generally well tolerated. 2 This combination can be accomplished with two pills using various fixed-dose combinations. 2
Specific approach:
- Replace carvedilol with lisinopril 10-40 mg daily or losartan 50-100 mg daily 2
- Unless the patient has compelling indications for beta-blocker therapy (coronary artery disease, heart failure with reduced ejection fraction, or recent myocardial infarction) 2
Monitoring Requirements
Check serum electrolytes and renal function within 1 month of adding spironolactone or increasing diuretic doses, with particular attention to potassium levels. 1 The combination of chlorthalidone (which lowers potassium) and spironolactone (which raises potassium) requires careful monitoring, though the risk of hyperkalemia is lower than when combining spironolactone with ACE inhibitors or ARBs. 1
Monitor for:
- Hyperkalemia - most important with spironolactone 1
- Hyponatremia - from chlorthalidone 1
- Elevated uric acid - dose-related effect of chlorthalidone 4
- Renal function changes - particularly creatinine 1
Optimization of Chlorthalidone Dosing
The current dose of chlorthalidone 25 mg is appropriate and should not be increased initially. 4 While the FDA label indicates doses can be increased to 50-100 mg daily for hypertension, increases in serum uric acid and decreases in serum potassium are dose-related over the 25-100 mg/day range, and dosages above 100 mg daily usually do not increase effectiveness. 4 Studies show that 25 mg daily provides equal efficacy to higher doses with fewer side effects and less potassium perturbation. 5
Important Caveats
- Never combine an ACE inhibitor with an ARB - this increases risk of hyperkalemia and renal dysfunction without additional blood pressure benefit 1
- Assess medication adherence before adding agents, as non-adherence is a common cause of treatment failure 3
- Review for interfering substances - NSAIDs can attenuate antihypertensive effects and should be discontinued if possible 3
- Consider bedtime dosing of at least one antihypertensive medication to improve 24-hour blood pressure control, particularly nighttime values 1
Target Blood Pressure
Aim for blood pressure 120-129/70-79 mmHg according to recent guidelines. 3