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CLINICAL STATEMENTS AND GUIDELINES Circulation. 2025;152:e114–e218. DOI: 10.1161/CIR.0000000000001356 September 16, 2025 e149 successful initially, it can be difficult to sustain optimal DBP levels. Therefore, if average DBP is ≥80 mm Hg after a 3- to 6-month trial, initiation of antihyperten sive therapy is advised as an adjunct to lifestyle inter ventions for adults aged ≥30 years, which was part of the inclusion criterion for the PREVER-Prevention trial.19 The AHA Life’s Essential 8 included DBP <80 mm Hg as optimal based on available epidemiologic data, with higher DBP associated with greater risk of subclinical and clinical CVD.28 While initiation of anti hypertensive therapy for adults <30 years for whom estimated risk models are limited, initiation of therapy could be considered after attempts at lifestyle inter vention have not achieved optimal BP levels, but data are limited in this age range. 5.2.3 Initial Medication Selection for Treatment of Primary Hypertension Recommendation for Initial Medication Selection for Treatment of Primary Hypertension Referenced studies that support the recommendation are summarized in the Evidence Table. COR LOE Recommendation 1 A 1. For adults initiating antihypertensive drug therapy, thiazide-type diuretics, long-acting dihydropyridine CCB, and ACEi or ARB are recommended as firstline therapy to prevent CVD.1,2 Synopsis Many antihypertensive agents are available (Table 13). When initiating pharmacological therapy, primary consid eration should be given to comorbidities (eg, coronary artery disease, HF, stroke, diabetes, CKD) for which specific BP-lowering medication classes are indicated (Section 5.3, “Comorbidities”). Strong RCT evidence sup ports 4 classes of first-line agents compared with pla cebo (thiazide-type diuretics, long-acting dihydropyridine CCB, and ACEi and ARB) due to their favorable profiles for BP lowering, CVD prevention, and tolerability.1–5 In a carefully designed head-to-head comparison of initial antihypertensive drug therapies, a long-acting thiazidetype diuretic was more effective than a CCB or ACEi for prevention of HF and slightly better than ACEi for pre vention of stroke.6 A meta-analysis of 50 RCTs with 58 head-to-head comparisons involving 247 006 individuals revealed subtle differences in efficacy between first-line agents.7 All other antihypertensive agents are considered secondary. BBs were less effective than first-line antihy pertensive classes in preventing strokes and had a less favorable side effect profile; therefore, they should be re served for adults with compelling indications.7 Recommendation-Specific Supportive Text 1 The primary goal of treatment should be to reduce BP to the target level, considering the underlying CVD risk and compelling indications. High-quality RCTs have demonstrated that 4 drug classes, thiazidetype diuretics, long-acting dihydropyridine CCB, ACEi and ARB, prevent CVD compared with placebo.1–5 In head-to-head comparisons of first-line therapy, differ ent drug classes show varying capacities to prevent specific CVD events.6,7 While there are subtle dif ferences among thiazide-type diuretics, long-acting dihydropyridine CCB, and ACEi and ARB, the gen eral pattern indicates a similar effect in preventing CVD. Likewise, the observed CVD prevention with these agents is similar to that expected on the basis of BP lowering.8 In a large pragmatic RCT compar ing HCTZ 25 mg to chlorthalidone 12.5 mg, switching from HCTZ to chlorthalidone did not lower the rates of MACE.9 The subgroup of patients with ASCVD had greater benefit with chlorthalidone than HCTZ; however, the design of the study made it difficult to exclude the possibility that choice of a longer-acting diuretic such as chlorthalidone is preferable to use of a shorter-acting agent such as HCTZ. 5.2.4 Choice of Initial Monotherapy Versus Initial Combination Drug Therapy Recommendations for Choice of Initial Monotherapy Versus Initial Combination Drug Therapy Referenced studies that support the recommendations are summarized in the Evidence Table. COR LOE Recommendations 1 B-R 1 In adults with stage 2 hypertension (SBP ≥ 140 mm Hg and DBP ≥90 mm Hg), initiation of antihypertensive drug therapy with 2 first-line agents of different classes, ideally in a single-pill combination (SPC), is recommended to improve BP control and adherence.1–6 2a C-EO 2 In adults with stage 1 hypertension (SBP 130- 139 mm Hg and DBP 80-89 mm Hg), initiation of antihypertensive drug therapy with a single firstline antihypertensive drug is reasonable, with dosage titration and sequential addition of other agents as needed to achieve BP control. 3: Harm A 3 In adults with hypertension, simultaneous use of an ACEi, ARB, and/or renin inhibitor in combination is not recommended due to the potential for harm.7–9 Synopsis Pharmacological agents are an integral tool in the treat ment of hypertension. As BP is regulated by several complementary biological systems, most patients require ≥2 antihypertensive medications to achieve BP control. Historically, a stepped-care approach was recommended, starting with monotherapy then titrating the dose or add ing a second agent as needed. No RCTs have compared initial stepped care with initial combination therapy. Com bining antihypertensive medications with complementary mechanisms enhances BP-lowering effects and may re duce side effects.2 For example, combining an RAS block er with a thiazide-type diuretic reduces the likelihood of hypokalemia or hyperkalemia, and combining an ACEi or ARB with a dihydropyridine CCB reduces the incidence Downloaded from http://ahajournals.org by on October 7, 2026