Antihypertensive Agents

Importance: Hypertension, defined as office systolic blood pressure (SBP) 130 mm Hg or greater and/or diastolic blood pressure 80 mm Hg or greater, affects 43.9% of women and 49.5% of men in the US. Approximately 19.7% of patients treated for hypertension have apparent resistant hypertension (blood pressure ≥130/80 mm Hg) despite using 3 or more antihypertensive medications, preferably a renin-angiotensin system blocker, a calcium channel blocker, and a thiazide-type diuretic, at maximally tolerated doses.

Observations: Approximately 10% of patients treated for hypertension have true resistant hypertension confirmed with home or 24-hour ambulatory blood pressure monitoring to exclude white-coat hypertension (approximately 37.5% of apparent resistant hypertension) and after excluding medication nonadherence (approximately 50%) and secondary hypertension such as primary aldosteronism (approximately 5%-25%). Conditions associated with resistant hypertension include obesity, diabetes, chronic kidney disease, and sleep apnea. Resistant hypertension is associated with increased risk of cardiovascular death vs controlled blood pressure at 5 years to 10 years (absolute risk increase, 10.3% [95% CI, 8.7%-12.1%]). Lifestyle modifications for resistant hypertension include a low-sodium diet (<1500 mg/d), reducing or avoiding alcohol, 150 min/wk or more of aerobic exercise, and weight loss. Illicit drugs (eg, cocaine) and medications that increase blood pressure (eg, nonsteroid anti-inflammatory drugs, serotonin-norepinephrine reuptake inhibitors) should be avoided. Sleep apnea should be treated when diagnosis is confirmed. Pharmacologic optimization includes use of combination tablets of antihypertensives; intensifying diuretic therapy by using chlorthalidone; and sequential addition of antihypertensive medications using evidence-based algorithms. In a meta-analysis of 20 studies (9 randomized clinical trials [RCTs] and 11 observational studies [331 participants]), use of antihypertensive therapies that combine 2 to 3 medications into a single formulation reduced SBP by -3.99 mm Hg (95% CI, -7.92 to -0.07) vs equivalent doses given separately. For patients with apparent or true resistant hypertension who have an estimated glomerular filtration rate of 45 mL/min/1.73 m2 or greater and a serum potassium level of 4.5 mmol/L or less, adding spironolactone (25-50 mg/d) compared with placebo lowers office SBP by -13.3 mm Hg (95% CI, -17.89 to -8.72 [4 RCTs]) and 24-hour ambulatory SBP by -8.46 mm Hg (95% CI, -12.54 to -4.38 [2 RCTs]) in a network meta-analysis of 24 RCTs (3485 patients with resistant hypertension). A meta-analysis of 10 RCTs (2478 participants) reported that compared with a sham procedure, catheter-based renal denervation, which disrupts the sympathetic nerves in the renal artery walls, decreased 24-hour ambulatory SBP by -4.4 mm Hg (95% CI, -6.1 to -2.7) and office SBP by -6.6 mm Hg (95% CI, -9.7 to -3.6).

Conclusions and relevance: True resistant hypertension affects 10% of patients treated for hypertension and is diagnosed after excluding white-coat hypertension, medication nonadherence, and secondary hypertension such as primary aldosteronism. First-line treatment includes lifestyle modifications, diuretic therapy with chlorthalidone, and combination tablets of antihypertensives. Spironolactone and renal denervation decrease blood pressure in patients with true resistant hypertension.

Author/s:

Michel Azizi, Wanpen Vongpatanasin, Naomi D. L. Fisher

Diagnosis and Management of Resistant Hypertension: A Review

Megan George — Tue, 24 Mar 2026 16:14:03 +0000

Date Added:

March 24, 2026

Journal/Publication:

JAMA

Publication Date:

March 23, 2026

URL:

Diagnosis and Management of Resistant Hypertension: A Review

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1001/jama.2026.1221

Keywords

blood pressure

Antihypertensive Agents

Resistant Hypertension

hypertension

Hyperaldosteronism

Anti-Inflammatory Agents

PMID (1):

41870448

MeSH

Blood Pressure Monitoring

Ambulatory

blood pressure

antihypertensive agents

renin-angiotensin system

resistant hypertension

hypertension

White Coat Hypertension

Hyperaldosteronism

Anti-Inflammatory Agents

A review of the evaluation and management of patients with resistant hypertension. James W. Mold, MD, MPH

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Author/s:

Michel Azizi, Wanpen Vongpatanasin, Naomi D L Fisher, Felix Mahfoud, Laurence Amar, Ajay J Kirtane

Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial

Aubrey Delammermore — Sat, 22 Oct 2022 05:00:00 +0000

Date Added:

October 22, 2022

Journal/Publication:

The Lancet

Publisher:

Elsevier

Publication Date:

October 11, 2022

Issue:

10361

Volume:

400

Pages:

1417-1425

URL:

Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial

Type:

Clinical Research Results

Format:

Article

DOI (1):

10.1016/S0140-6736(22)01786-X

Keywords

Intention to Treat Analysis

Antihypertensive Agents

Cardiovascular Diseases

Surveys and Questionnaires

United Kingdom

PMID (1):

36240838

MeSH

antihypertensive agents

myocardial infarction

Time and Motion Studies

hypertension

stroke

In this large RCT, evening dosing of antihypertensive drugs was no better than morning dosing in regard to cardiovascular outcomes. James W. Mold, MD, MPH

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Background: Studies have suggested that evening dosing with antihypertensive therapy might have better outcomes than morning dosing. The Treatment in Morning versus Evening (TIME) study aimed to investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension.

Methods: The TIME study is a prospective, pragmatic, decentralised, parallel-group study in the UK, that recruited adults (aged ≥18 years) with hypertension and taking at least one antihypertensive medication. Eligible participants were randomly assigned (1:1), without restriction, stratification, or minimisation, to take all of their usual antihypertensive medications in either the morning (0600-1000 h) or in the evening (2000-0000 h). Participants were followed up for the composite primary endpoint of vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal stroke. Endpoints were identified by participant report or record linkage to National Health Service datasets and were adjudicated by a committee masked to treatment allocation. The primary endpoint was assessed as the time to first occurrence of an event in the intention-to-treat population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants who submitted at least one follow-up questionnaire. The study is registered with EudraCT (2011-001968-21) and ISRCTN (18157641), and is now complete.

Findings: Between Dec 17, 2011, and June 5, 2018, 24 610 individuals were screened and 21 104 were randomly assigned to evening (n=10 503) or morning (n=10 601) dosing groups. Mean age at study entry was 65·1 years (SD 9·3); 12 136 (57·5%) participants were men; 8968 (42·5%) were women; 19 101 (90·5%) were White; 98 (0·5%) were Black, African, Caribbean, or Black British (ethnicity was not reported by 1637 [7·8%] participants); and 2725 (13·0%) had a previous cardiovascular disease. By the end of study follow-up (March 31, 2021), median follow-up was 5·2 years (IQR 4·9-5·7), and 529 (5·0%) of 10 503 participants assigned to evening treatment and 318 (3·0%) of 10 601 assigned to morning treatment had withdrawn from all follow-up. A primary endpoint event occurred in 362 (3·4%) participants assigned to evening treatment (0·69 events [95% CI 0·62-0·76] per 100 patient-years) and 390 (3·7%) assigned to morning treatment (0·72 events [95% CI 0·65-0·79] per 100 patient-years; unadjusted hazard ratio 0·95 [95% CI 0·83-1·10]; p=0·53). No safety concerns were identified.

Interpretation: Evening dosing of usual antihypertensive medication was not different from morning dosing in terms of major cardiovascular outcomes. Patients can be advised that they can take their regular antihypertensive medications at a convenient time that minimises any undesirable effects.

Funding: British Heart Foundation.

Author/s:

Mackenzie, I. S., Rogers, A., Poulter, N. R., Williams, B., Brown, M. J., Webb, D. J., Ford, I., Rorie, D. A., Guthrie, G., Grieve, J. W. K., Pigazzani, F., Rothwell, P. M., Young, R., McConnachie, A., Struthers, A. D., Lang, C. C., MacDonald, T. M.