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CLINICAL STATEMENTS AND GUIDELINES September 16, 2025 Circulation. 2025;152:e114–e218. DOI: 10.1161/CIR.0000000000001356 e152 and severity of lower leg swelling. Combination therapy is more effective, efficient, and consistent in lowering BP and improves adherence when using an SPC compared with stepped-care therapy.10 However, a stepped-care approach can be effective for BP lowering if wellexecuted.11 Exceptions include stage 1 hypertension, where some patients can achieve and maintain BP control with a single agent, especially those with initial BP close to target. Initial combination therapy is recom mended for stage 2 hypertension and some high-risk patients with stage 1 hypertension (eg, non-Hispanic Black adults, ASCVD risk >7.5%) using 2 agents from different classes, preferably in an SPC to improve ad herence and BP control (Section 5.2.5, “Antihypertensive Medication Adherence Strategies”).1–3 Few RCTs have compared different combinations head-to-head. Avail able RCT evidence supports using an RAS blocker with either a thiazide-type diuretic or a dihydropyridine CCB as initial therapy. Recommendation-Specific Supportive Text 1 Because most patients with hypertension require multiple agents for control of their BP, for those who are candidates for initial combination therapy (nonfrail adults with SBP ≥20 mm Hg and DBP ≥10 mm Hg from target), starting treatment with SPCs rather than equivalent free-pill combinations improves adherence (Table 14).4,5 Moreover, adults with hypertension on SPCs have fewer cardiovascular events and all-cause deaths than those on equivalent multiple-pill combi nation therapy in observational studies.6 Evidence favoring this approach comes mostly from studies showing greater BP lowering with SPC agents than with single agents, with higher adherence rates.1,2,12–14 Several smaller RCTs have demonstrated that lowdose combinations of 3 or 4 drugs together reduces BP more effectively than monotherapy over 3 to 6 months of treatment; however, none of these trials have evaluated CVD prevention.3 In general, initial combination therapy with 2 drugs is reasonable in adults with stage 2 hypertension and those at high CVD risk. However, BP-lowering medications should be carefully initiated and monitored in older patients because hypotension or orthostatic hypotension (OH) may develop. In most cases, SPCs are a cost-effective alternative to multiple pill combination therapy, and longer follow-up intervals extend the time for inten sification of each medication and addition of the next medication in stepped-care treatment.15,16 Further, as SPCs are not available with every possible dose com bination, in some cases the use of separate agents may be more or equally efficient. 2. Although most patients with stage 2 hyperten sion require at least 2 classes of antihypertensive agents, the stepped-care approach, defined by the initiation of antihypertensive drug therapy with a single agent followed by sequential titration of the dose and addition of other agents if needed, is a Class Drug Usual Dose, Range (mg/d)∗ Daily Frequency Comments Central alpha-2-agonist and other centrally acting drugs Clonidine oral 0.1-0.8 2 These are generally reserved as last-line choices because of significant CNS adverse effects, especially in older adults. Avoid abrupt discontinuation of clonidine, which may in duce hypertensive crisis. Clonidine must be tapered to avoid rebound hyperten sion. Clonidine patch 0.1-0.3 1 weekly Methyldopa 250-1000 2 Guanfacine 0.5-2 1 Direct vasodilators Hydralazine 100-200 2 or 3 These are associated with sodium and water retention and reflex tachycardia and should be used with a diuretic and beta blocker. Hydralazine is associated with a drug-induced lupus-like syndrome at higher doses. Minoxidil is associated with hirsutism and requires a loop diuretic. Minoxidil can induce pericardial effusion. Minoxidil 5-40 1-2 Dual endothelin receptor antagonist Aprocitentan 12.5 1 Associated with mild-to-moderate fluid retention usually occurring within the first 4-6 wks of therapy. Indicated as add-on therapy for patients whose BP is not adequately controlled on other antihypertensive medica tions. Avoid use in pregnancy. Modified with permission from Whelton et al.10 Copyright 2018 American College of Cardiology Foundation and American Heart Association, Inc., and with permission from Chobanian et al.11 Copyright 2003 American Heart Association, Inc. ACEi indicates angiotensin-converting-enzyme inhibitors; ARB, angiotensin receptor blockers, BP, blood pressure; CCB, calcium channel blocker; CNS, central ner vous system; CKD, chronic kidney disease; CHD, coronary heart disease; GFR, glomerular filtration rate; HF, heart failure; HFrEF, HF with reduced rejection fraction; and K+, potassium. Table 13. Continued Downloaded from http://ahajournals.org by on October 7, 2026