What is the next step for a patient with uncontrolled hypertension who is already on maximum dual antihypertensive therapy?

Management of Uncontrolled Hypertension on Maximum Dual Therapy

For patients with uncontrolled hypertension already on maximum dual therapy, the next step is to add a thiazide/thiazide-like diuretic as a third agent if not already included, followed by spironolactone as the preferred fourth-line agent for resistant hypertension. 1

Assessment Before Adding Medications

• Verify proper blood pressure measurement technique using a validated device with appropriate cuff size, and confirm elevated readings with home or ambulatory blood pressure monitoring 1
• Check medication adherence, as this is a common cause of inadequate blood pressure control before adding additional agents 1
• Ensure current medications are at maximum tolerated doses before adding new agents 1
• Allow sufficient time (2-4 weeks) for full effect of dose adjustments before making further changes 1

Stepwise Medication Addition Algorithm

Third-Line Agent

• Add a thiazide/thiazide-like diuretic as the third agent if not already included in the regimen 1
• Target blood pressure should be <130/80 mmHg for most patients, but may be individualized for elderly patients based on frailty 1
• Aim to achieve target blood pressure within 3 months of treatment initiation 1

Fourth-Line Agent

• Add spironolactone as the preferred fourth-line agent for resistant hypertension 1, 2

  • Starting dose of 25 mg once daily for hypertension 3
  • Monitor serum potassium before initiating therapy, within the first week, and at one month after starting treatment 4
  • Contraindicated in patients with serum potassium >5.5 mEq/L, creatinine clearance ≤30 mL/min, or concomitant use of strong CYP3A inhibitors 4

• Alternative fourth-line agents if spironolactone is contraindicated or not tolerated:

  • Eplerenone (starting at 50 mg once daily, can increase to 50 mg twice daily) 4
  • Amiloride 1
  • Clonidine 1
  • Beta-blocker 1

Special Population Considerations

• For Black patients, ensure that at least one agent in the regimen is either a calcium channel blocker or a thiazide diuretic 5
• For patients with diabetes mellitus and proteinuria, ensure the regimen includes an ACEI or ARB 5
• For patients with chronic kidney disease and proteinuria, include an ACEI or ARB plus a thiazide diuretic or calcium channel blocker 5

Monitoring and Follow-up

• Assess serum potassium and renal function within 3-7 days when adding mineralocorticoid receptor antagonists like spironolactone or eplerenone 4
• Continue to monitor blood pressure response and adjust medications as needed 1
• If blood pressure remains uncontrolled despite adherence to a four-drug regimen including a diuretic, refer to a provider with hypertension expertise 1

Common Pitfalls to Avoid

• Not checking for medication adherence before adding additional agents 1
• Inadequate dosing of medications before adding new agents 1
• Not allowing sufficient time for full effect of dose adjustments before further changes 1
• Overlooking the risk of hyperkalemia when adding spironolactone or eplerenone, especially in patients with impaired renal function, diabetes, or those taking ACEIs or ARBs 4

Remember that approximately one-fourth to one-third of patients will require three or more drugs to achieve adequate blood pressure control 6, and triple-combination therapy has been shown to produce greater BP reductions compared to dual therapies 6.