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CLINICAL STATEMENTS AND GUIDELINES September 16, 2025 Circulation. 2025;152:e114–e218. DOI: 10.1161/CIR.0000000000001356 e154 5.2.6 Medication Interactions Synopsis When designing an antihypertensive regimen that minimizes unwanted adverse effects while maximiz ing beneficial effects for patients taking more than 1 medication (Tables 13 and 14), knowledge of pharmacology and drug-drug interactions is essen tial. Drug-drug interactions are categorized as either pharmacokinetic (when 1 medication affects the ab sorption, metabolism, distribution, or elimination of another) or pharmacodynamic (when 1 medication affects the end-pharmacological response to another medication without impacting the drug’s disposition within the body). Important pharmacokinetic interac tions relevant to hypertension management involve the CYP3A4 pathway; verapamil and diltiazem are both substrates and inhibitors of CYP3A4 and can alter the metabolism of other medications processed through this pathway. Table 16 summarizes other key clinical pharmacokinetic drug-drug interactions. Ex amples of beneficial pharmacodynamic interactions include the combination of an RAS inhibitor with a thiazide-type diuretic to minimize diuretic-induced hypokalemia, or a dihydropyridine CCB with an RAS inhibitor to reduce the incidence or severity of lower extremity edema. Conversely, combining drugs with overlapping mechanisms, like ACEi and ARB or direct renin inhibitors, leads to an increased risk of hyperka lemia, an adverse pharmacodynamic interaction. Table 17 lists other key pharmacodynamic drug-drug inter actions affecting antihypertensive medications. 5.2.7 BP Goal for Patients With Hypertension Recommendations for BP Goal for Patients With Hypertension Referenced studies that support recommendations are summarized in the Evidence Table. COR LOE Recommendations 1 A 1 In adults with confirmed hypertension who are at increased risk* for CVD, an SBP goal of at least <130 mm Hg, with encouragement to achieve SBP <120 mm Hg, is recommended to reduce the risk of cardiovascular events and total mortality.1–4 2b B-NR 2 In adults with confirmed hypertension who are not at increased risk* for CVD, an SBP goal of <130 mm Hg, with encouragement to achieve SBP <120 mm Hg, may be reasonable to reduce risk of further elevation of BP.5 1 B-R 3 In adults with confirmed hypertension who are at increased risk* for CVD, a DBP target of <80 mm Hg is recommended to reduce the risk of cardiovascular events and total mortality.6 2b B-NR 4 In adults with confirmed hypertension who are not at increased risk* for CVD, a DBP target of <80 mm Hg may be reasonable to reduce the risk of cardiovascular events.5 *Increased risk is defined as a 10-year predicted risk for CVD events of ≥7.5% using PREVENT. Synopsis In observational studies, BP is associated with CVD risk in a progressive, log-linear fashion from low to high levels7–9 (eg, SBP 100-180 mm Hg), suggesting the likelihood of CVD benefits with more intensive treatment. In adults at high risk for CVD, RCTs, including those that randomized adults to different BP treatment targets,2,4,10–15 and clinical trials and meta-analyses support more intensive treatment to prevent CVD.1,13,16–21 The evidence to support an SBP goal <130 mm Hg is strong.1 There is also evidence for an SBP goal <120 mm Hg versus <140 mm Hg, but this is based on a smaller, albeit growing, number of trials.1,10 Adverse effects of intensive antihypertensive therapy have received less careful scrutiny in clinical trials. Hypotension, syncope, injurious falls, electrolyte abnormalities, and a reduction in eGFR are the most commonly recognized adverse events, but they are infrequent and usually mild.1 Overall, clinical trials provide strong support for an SBP goal <130 mm Hg and, when feasible, SBP <120 mm Hg. Generalization from clinical trials to clinical practice is challenging, underscoring the need for careful monitoring of patients receiving intensive antihypertensive therapy. Individualization of the BP target may be required in the minority of patients who have difficulty tolerating the an tihypertensive treatment, experience side effects, have limited life expectancy, or have other clinical features that warrant a less intensive treatment approach. Clinical judgment and shared decision-making are appropriate in selecting the intensity of antihypertensive therapy in indi vidual patients, and careful monitoring for adverse conse quences is warranted. Achievement of target BP should be based on an average of ≥2 readings at ≥2 visits, not on an individual BP measurement. Limited clinical trial results are available to guide the level of antihypertensive inten sity in adults with hypertension who are not at high risk for CVD, but on balance, an SBP/DBP target of <130/80 mm Hg seems reasonable. Shared decision-making by cli nicians, patients, and their caregivers for BP goals should be utilized when the patient has a limited life expectancy or is institutionalized due to high burden of frailty and co morbidity with limited life expectancy. Recommendation-Specific Supportive Text 1 In adults at high risk for CVD, 8 trials have compared outcomes in participants randomized to an SBP tar get <130 mm Hg or to a higher SBP. In a meta-anal ysis that included 7 of these trials, randomization to an SBP <130 mm Hg resulted in significant reduc tions in CVD (including reductions in stroke, CHD, HF, and CVD mortality) and all-cause mortality.1 Hypotension, syncope, injurious falls, electrolyte abnormalities, and acute kidney injury (AKI) were significantly more common in those randomized to Downloaded from http://ahajournals.org by on October 7, 2026