The addition of chlorthalidone is the most appropriate next step in management in this patient who has uncontrolled hypertension with evidence of end-organ damage (left ventricular hypertrophy, chronic kidney disease, and retinopathy) despite being on three medications. However, he does not meet the definition of resistant hypertension, which is defined by blood pressure readings not at target despite three agents, one of which must be a diuretic. Persistent volume expansion, even if not sufficient to produce clinically evident edema, contributes significantly to hypertension; because of this, use of diuretics is almost always required to achieve adequate blood pressure control in patients with resistant blood pressure. Therefore, the addition of a diuretic such as chlorthalidone is appropriate for this patient before other drugs are added. Chlorthalidone is often preferred over other thiazide-type diuretics primarily due to its higher potency and longer duration of action.

Although limited data exist regarding the most effective medication regimen for patients requiring multi-drug therapy, a reasonable approach is to use medications recommended by hypertension treatment guidelines that have different mechanisms of action, with consideration of other agents with an antihypertensive effect indicated for treatment of comorbid conditions (such as a β-blocker for atrial fibrillation). For example, in addition to diuretic therapy, the combination of a long-acting dihydropyridine calcium channel blocker with an ACE inhibitor or angiotensin receptor blocker is often effective and generally well tolerated.

Vasodilator agents (hydralazine or minoxidil) and centrally acting agents (clonidine or guanfacine) may be effective, although side effects are common. Therefore, these medications are more commonly used as add-on therapy to other guideline-recommended agents and would not be an appropriate choice in this patient who is not currently on a diuretic. Additionally, minoxidil promotes sodium retention and is almost always given with a diuretic. Its use in this patient who is not taking a diuretic would not be appropriate.

Switching from nifedipine to amlodipine would not be expected to significantly improve blood pressure because both drugs are in the same class.