hypertension

Management of Orthostatic Hypotension: A Review

Author/s: 
David Moloney, Ayman Youssef, Luis E. Okamoto

Importance: Orthostatic hypotension is a common but underrecognized condition that increases with age and is associated with a lower quality of life, falls, and increased mortality. The frequent coexistence of supine hypertension and postprandial hypotension with orthostatic hypotension makes it a challenging condition to manage.

Observations: Testing for orthostatic hypotension should be done in patients with orthostatic symptoms (eg, vision changes and dizziness that occur only when upright and improve when seated or lying down), as well as asymptomatic patients in high-risk groups such as adults with frailty who are older than 70 years, individuals with neurodegenerative or autonomic disorders, and patients with unexplained falls. Patients with orthostatic hypotension should be screened for postprandial hypotension and supine hypertension to inform the treatment approach. Nonpharmacological strategies, such as medication review, increased salt and fluid intake, compression garments, and behavioral modifications, serve as fundamental approaches to treat orthostatic hypotension. Midodrine and droxidopa are the only US Food and Drug Administration-approved medications for orthostatic hypotension, but other medications (eg, fludrocortisone, atomoxetine, pyridostigmine) are used off label as part of an individualized treatment plan. Treatment targets in orthostatic hypotension are focused not on blood pressure measurements but on symptom relief and fall prevention.

Conclusions and relevance: All patients with orthostatic symptoms-along with other select patient groups-should be evaluated for orthostatic hypotension. Nonpharmacological treatments are first line, and medication decisions should be tailored based on clinical presentation and relevant comorbidities.

Diagnosis and Management of Resistant Hypertension: A Review

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

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.

Management of Hypertension in Adults

Author/s: 
Amber E Johnson, Christopher D Jackson, Jason T Alexander

Hypertension is the leading modifiable risk factor worldwide for ASCVD, and approximately half of US adults have hypertension.1 Uncontrolled BP contributes to heart failure, stroke, atrial fibrillation, and sudden cardiac death and is associated with development of kidney failure and dementia.2 This guideline was designed to provide clinicians with a risk stratification approach to managing BP. This synopsis highlights key guideline recommendations.

Approach to pelvic venous disorders

Author/s: 
Andrew D Brown

Objective: To provide a practical guide to help family physicians recognize, diagnose, and manage patients with pelvic venous disorders (PeVDs), often overlooked as causes of chronic pelvic pain and varicose veins.

Sources of information: This review is based on guidelines from the American Venous Forum, the Society for Vascular Surgery, the American Vein and Lymphatic Society, the Society of Interventional Radiology, and the European Society for Vascular Surgery.

Main message: PeVDs are common, though frequently misdiagnosed, causes of chronic pelvic pain and varicose veins predominantly in female patients. These conditions arise from venous reflux or obstruction, which can cause varicose veins and venous hypertension in the renal hilum, pelvis, perineum, and lower extremities. Family physicians should recognize the clinical signs of PeVDs and use appropriate imaging to confirm diagnoses. Interventional treatments, including embolization and stenting, are effective for symptom management and improving patient outcomes.

Conclusion: Early recognition of patients with PeVDs by family physicians is crucial for timely and effective treatment. By using appropriate diagnostic tools and making timely referrals, physicians can substantially improve patients' quality of life.

Long-Term Anticoagulation Discontinuation After Catheter Ablation for Atrial Fibrillation: The ALONE-AF Randomized Clinical Trial

Author/s: 
Daehoon Kim, MD, Jaemin Shim, MD, Eue-Keun Choi, MD

Importance: Data from randomized clinical trials on a long-term anticoagulation strategy for patients after catheter-based ablation for atrial fibrillation (AF) are lacking.

Objective: To evaluate whether discontinuing oral anticoagulant therapy provides superior clinical outcomes compared with continuing oral anticoagulant therapy in patients without documented atrial arrhythmia recurrence after catheter ablation for AF.

Design, setting, and participants: A randomized clinical trial including 840 adult patients (aged 19-80 years) who were enrolled and randomized from July 28, 2020, to March 9, 2023, at 18 hospitals in South Korea. Enrolled patients had at least 1 non-sex-related stroke risk factor (determined using the CHA2DS2-VASc score [range, 0-9]) and no documented recurrence of atrial arrhythmia for at least 1 year after catheter ablation for AF. The CHA2DS2-VASc score is used as an assessment of stroke risk among patients with AF (calculated using point values for congestive heart failure, hypertension, ≥75 years of age, diabetes, stroke or transient ischemic attack, vascular disease, between 65 and 74 years of age, and sex category). The date of final follow-up was June 4, 2025.

Interventions: The patients were randomly assigned in a 1:1 ratio to discontinue oral anticoagulant therapy (n = 417) or continue oral anticoagulant therapy (with direct oral anticoagulants; n = 423).

Main outcomes and measures: The primary outcome was the first occurrence of a composite of stroke, systemic embolism, and major bleeding at 2 years. Individual components of the primary outcome (such as ischemic stroke and major bleeding) were assessed as secondary outcomes.

Results: Of the 840 adults randomized, the mean age was 64 (SD, 8) years, 24.9% were women, the mean CHA2DS2-VASc score was 2.1 (SD, 1.0), and 67.6% had paroxysmal AF. At 2 years, the primary outcome occurred in 1 patient (0.3%) in the discontinue oral anticoagulant therapy group vs 8 patients (2.2%) in the continue oral anticoagulant therapy group (absolute difference, -1.9 percentage points [95% CI, -3.5 to -0.3]; P = .02). The 2-year cumulative incidence of ischemic stroke was 0.3% in the discontinue oral anticoagulant therapy group vs 0.8% in the continue oral anticoagulant therapy group (absolute difference, -0.5 percentage points [95% CI, -1.6 to 0.6]). Major bleeding occurred in 0 patients in the discontinue oral anticoagulant therapy group vs 5 patients (1.4%) in the continue oral anticoagulant therapy group (absolute difference, -1.4 percentage points [95% CI, -2.6 to -0.2]).

Conclusions and relevance: Among patients without documented atrial arrhythmia recurrence after catheter ablation for AF, discontinuing oral anticoagulant therapy resulted in a lower risk for the composite outcome of stroke, systemic embolism, and major bleeding vs continuing direct oral anticoagulant therapy.

Trial registration: ClinicalTrials.gov Identifier: NCT04432220.

Patent Foramen Ovale and Stroke A Review

Author/s: 
David M. Kent, Andy Y. Wang

Importance: A patent foramen ovale (PFO), an opening between the right and left atria during normal fetal development that fails to close after birth, is present in approximately 25% of all adults. Paradoxical embolism, a venous thromboembolism that travels to the systemic circulation typically through a PFO, accounts for about 5% of all strokes and 10% of strokes in younger patients.

Observations: Approximately 50% of patients 60 years or younger with an embolic stroke of undetermined source (cryptogenic stroke) have a PFO, compared with 25% of the general population. The Risk of Paradoxical Embolism (RoPE) score incorporates clinical characteristics (age, history of stroke or transient ischemic attack, diabetes, hypertension, smoking, cortical infarct on imaging) to predict the likelihood that embolic stroke of undetermined source was caused by a PFO. Among patients in the lowest RoPE score category (score <3), PFO prevalence was similar to that in the general population (23%), while PFO prevalence was 77% in patients with a RoPE score of 9 or 10. The PFO-Associated Stroke Causal Likelihood (PASCAL) classification system combines the RoPE score and anatomical criteria from echocardiography (large shunt, atrial septal aneurysm) to classify PFO as the “probable,” “possible,” or “unlikely” cause of otherwise cryptogenic stroke. PFO closure reduces recurrent ischemic stroke in patients 60 years or younger with cryptogenic stroke. In a pooled analysis of 6 trials (3740 patients), the annualized incidence of stroke over a median follow-up of 57 months was 0.47% (95% CI, 0.35%-0.65%) with PFO closure vs 1.09% (95% CI, 0.88%-1.36%) with medical therapy (adjusted hazard ratio, 0.41 [95% CI, 0.28-0.60]). However, the benefits and harms of closure were highly heterogeneous across the trial populations. In patients categorized as PASCAL “probable” (ie, younger patients without vascular risk factors and high-risk PFO anatomical features), there was a 90% decreased relative rate of recurrent ischemic stroke after PFO closure at 2 years (hazard ratio, 0.10 [95% CI, 0.03-0.35]; absolute risk reduction, 2.1% [95% CI, 0.9%-3.4%]). PASCAL “unlikely” patients (eg, older patients with vascular risk factors and no high-risk PFO anatomical features) did not have a lower recurrent stroke rate with PFO closure but had higher risk of procedure- and device-related adverse events, such as atrial fibrillation.

Conclusions and Relevance: Patent foramen ovale is present in approximately 25% of all adults and is a common cause of stroke in young and middle-aged patients. The PASCAL classification system can help guide patient selection for PFO closure. Percutaneous PFO closure substantially reduces the risk of stroke recurrence in well-selected patients younger than 60 years after cryptogenic stroke.

What Is Atrial Fibrillation?

Author/s: 
Rebecca Voelker

Atrial fibrillation is an abnormal heart rhythm that can cause stroke, heart failure, heart attack, chronic kidney disease, dementia, and death.

Atrial fibrillation is classified as paroxysmal (intermittent episodes lasting 7 days or less), persistent (lasting more than 7 days), long-standing persistent (lasting more than 1 year), or permanent.1

In the US, atrial fibrillation affects about 10.55 million people and is more common among men than women. Other risk factors include older age, smoking, high blood pressure, diabetes, heart disease, high alcohol consumption, sleep apnea, an overactive thyroid gland, and possibly genetic factors.

Arm Position and Blood Pressure Readings: The ARMS Crossover Randomized Clinical Trial

Author/s: 
Hairong Liu, Di Zhao, Ahmed Sabit

Importance: Guidelines for blood pressure (BP) measurement recommend arm support on a desk with the midcuff positioned at heart level. Still, nonstandard positions are used in clinical practice (eg, with arm resting on the lap or unsupported on the side).

Objective: To determine the effect of different arm positions on BP readings.

Design, setting, and participants: This crossover randomized clinical trial recruited adults between the ages of 18 and 80 years in Baltimore, Maryland, from August 9, 2022, to June 1, 2023.

Intervention: Participants were randomly assigned to sets of triplicate BP measurements with the arm positioned in 3 ways: (1) supported on a desk (desk 1; reference), (2) hand supported on lap (lap), and (3) arm unsupported at the side (side). To account for intrinsic BP variability, all participants underwent a fourth set of BP measurements with the arm supported on a desk (desk 2).

Main outcomes and measures: The primary outcomes were the difference in differences in mean systolic BP (SBP) and diastolic BP (DBP) between the reference BP (desk 1) and the 2 arm support positions (lap and side): (lap or side - desk 1) - (desk 2 - desk 1). Results were also stratified by hypertensive status, age, obesity status, and access to health care within the past year.

Results: The trial enrolled 133 participants (mean [SD] age, 57 [17] years; 70 [53%] female); 48 participants (36%) had SBP of 130 mm Hg or higher, and 55 participants (41%) had a body mass index (calculated as weight in kilograms divided by height in meters squared) of 30 or higher. Lap and side positions resulted in statistically significant higher BP readings than desk positions, with the difference in differences as follows: lap, SBP Δ 3.9 (95% CI, 2.5-5.2) mm Hg and DBP Δ 4.0 (95% CI, 3.1-5.0) mm Hg; and side, SBP Δ 6.5 (95% CI, 5.1-7.9) mm Hg and DBP Δ 4.4 (95% CI, 3.4-5.4) mm Hg. The patterns were generally consistent across subgroups.

Conclusion and relevance: This crossover randomized clinical trial showed that commonly used arm positions (lap or side) resulted in substantial overestimation of BP readings and may lead to misdiagnosis and overestimation of hypertension.

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

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.

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.

Effects of salt substitutes on clinical outcomes: a systematic review and meta-analysis

Author/s: 
Yin, X., Rodgers, A., Perkovic, A., Huang, L., Li, K., Yu, J., Wu, Y., Wu, J. H. Y., Marklund, M., Huffman, M. D., Miranda, J. J., Di Tanna, G. L., Labarthe, D., Elliott, P., Tian, M., Neal, B.

Objectives The Salt Substitute and Stroke Study (SSaSS) recently reported blood pressure-mediated benefits of a potassium-enriched salt substitute on cardiovascular outcomes and death. This study assessed the effects of salt substitutes on a breadth of outcomes to quantify the consistency of the findings and understand the likely generalisability of the SSaSS results.

Methods We searched PubMed, Embase and the Cochrane Library up to 31 August 2021. Parallel group, step-wedge or cluster randomised controlled trials reporting the effect of salt substitute on blood pressure or clinical outcomes were included. Meta-analyses and metaregressions were used to define the consistency of findings across trials, geographies and patient groups.

Results There were 21 trials and 31 949 participants included, with 19 reporting effects on blood pressure and 5 reporting effects on clinical outcomes. Overall reduction of systolic blood pressure (SBP) was −4.61 mm Hg (95% CI −6.07 to −3.14) and of diastolic blood pressure (DBP) was −1.61 mm Hg (95% CI −2.42 to −0.79). Reductions in blood pressure appeared to be consistent across geographical regions and population subgroups defined by age, sex, history of hypertension, body mass index, baseline blood pressure, baseline 24-hour urinary sodium and baseline 24-hour urinary potassium (all p homogeneity >0.05). Metaregression showed that each 10% lower proportion of sodium choloride in the salt substitute was associated with a −1.53 mm Hg (95% CI −3.02 to −0.03, p=0.045) greater reduction in SBP and a −0.95 mm Hg (95% CI −1.78 to −0.12, p=0.025) greater reduction in DBP. There were clear protective effects of salt substitute on total mortality (risk ratio (RR) 0.89, 95% CI 0.85 to 0.94), cardiovascular mortality (RR 0.87, 95% CI 0. 81 to 0.94) and cardiovascular events (RR 0.89, 95% CI 0.85 to 0.94).

Conclusions The beneficial effects of salt substitutes on blood pressure across geographies and populations were consistent. Blood pressure-mediated protective effects on clinical outcomes are likely to be generalisable across population subgroups and to countries worldwide.

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