A randomized controlled crossover trial evaluating differential responses to antihypertensive drugs (used as mono- or dual therapy) on the basis of ethnicity: The comparIsoN oF Optimal Hypertension RegiMens; part of the Ancestry Informative Markers in HYpertension program-AIM-HY INFORM trial.

BACKGROUND: Ethnicity, along with a variety of genetic and environmental factors, is thought to influence the efficacy of antihypertensive therapies. Current UK guidelines use a "black versus white" approach; in doing so, they ignore the United Kingdom's largest ethnic minority: Asians from South Asia. STUDY DESIGN: The primary purpose of the AIM-HY INFORM trial is to identify potential differences in response to antihypertensive drugs used as mono- or dual therapy on the basis of self-defined ethnicity. A multicenter, prospective, open-label, randomized study with 2 parallel, independent trial arms (mono- and dual therapy), AIM-HY INFORM plans to enroll a total of 1,320 patients from across the United Kingdom. Those receiving monotherapy (n = 660) will enter a 3-treatment (amlodipine 10 mg od; lisinopril 20 mg od; chlorthalidone 25 mg od), 3-period crossover, lasting 24 weeks, whereas those receiving dual therapy (n = 660) will enter a 4-treatment (amlodipine 5 mg od and lisinopril 20 mg od; amlodipine 5 mg od and chlorthalidone 25 mg od; lisinopril 20 mg od and chlorthalidone 25 mg od; amiloride 10 mg od and chlorthalidone 25 mg od), 4-period crossover, lasting 32 weeks. Equal numbers of 3 ethnic groups (white, black/black British, and Asian/Asian British) will ultimately be recruited to each of the trial arms (ie, 220 participants per ethnic group per arm). Seated, automated, unattended, office, systolic blood pressure measured 8 weeks after each treatment period begins will serve as the primary outcome measure. CONCLUSION: AIM-HY INFORM is a prospective, open-label, randomized trial which aims to evaluate first- and second-line antihypertensive therapies for multiethnic populations.

Vascular smooth muscle cells from small human omental arteries express P2X1 and P2X4 receptor subunits.

Stimulation of P2X receptors by ATP in vascular smooth muscle cells (VSMCs) is proposed to mediate vascular tone. However, understanding of P2X receptor-mediated actions in human blood vessels is limited, and therefore, the current work investigates the role of P2X receptors in freshly isolated small human gastro-omental arteries (HGOAs). Expression of P2X1 and P2X4 receptor subunit messenger RNA (mRNA) and protein was identified in individual HGOA VSMCs using RT-PCR and immunofluorescent analysis and using Western blot in multi-cellular preparations. ATP of 10 µmol/l and αß-meATP of 10 µmol/l, a selective P2X receptor agonist, evoked robust increases in [Ca(2+)]i in fluo-3-loaded HGOA VSMCs. Pre-incubation with 1 µmol/l NF279, a selective P2X receptor antagonist, reduced the amplitude of αß-meATP-induced increase in [Ca(2+)]i by about 70 %. ATP of 10 µmol/l and αß-meATP of 10 µmol/l produced similar contractile responses in segments of HGOA, and these contractions were greatly reduced by 2 µmol/l NF449, a selective P2X receptor inhibitor. These data suggest that VSMCs from HGOA express P2X1 and P2X4 receptor subunits with homomeric P2X1 receptors likely serving as the predominant target for extracellular ATP.

Evaluation of a specialist nurse-led hypertension clinic with consultant backup in two inner city general practices: randomized controlled trial.

BACKGROUND: Although practice nurses are increasingly involved in hypertension management, there is little robust evidence of effectiveness. OBJECTIVE: To evaluate the effect of a specialist nurse-led hypertension clinic with consultant backup on change in systolic blood pressure. DESIGN: Randomized trial. SETTING: Two inner city general practices. Participants. Three hundred and fifty-three patients, mean age 62 years (range 18-99), with last recorded blood pressure ≥ British Hypertension Society audit standard were randomly allocated to the nurse-led clinic or usual care. Intervention. Patients received a letter informing them that their last blood pressure was over target and inviting them to the clinic. After assessment at the clinic, the nurse discussed any changes in anti-hypertensive treatment with a visiting consultant and the patient's GP, and followed up the patient over 6 months until blood pressure targets were achieved. MAIN OUTCOME MEASURE: Reduction in systolic blood pressure, assessed using two audits of the practices' computerized records where blood pressure was measured independently by practice staff before and after the intervention period. RESULTS: Follow-up was 89% (313/353). There was greater reduction in systolic blood pressure in the clinic group (n = 144) than usual care group (n = 169, adjusted difference 4.4 mmHg; 95% CI 0.7 to 8.2). Of 167 patients randomly selected for the clinic, 91 (55%) attended, 49 had blood pressure above target when measured according to protocol and 26 had their anti-hypertensive treatment intensified by their GP. CONCLUSION: Invitation to a specialist nurse-led hypertension clinic with consultant back up was associated with reduced systolic blood pressure.

Home blood pressure monitoring with nurse-led telephone support among patients with hypertension and a history of stroke: a community-based randomized controlled trial.

BACKGROUND: Adequate control of blood pressure reduces the risk of recurrent stroke. We conducted a randomized controlled study to determine whether home blood pressure monitoring with nurse-led telephone support would reduce blood pressure in patients with hypertension and a history of stroke. METHODS: We recruited 381 participants (mean age 72 years) from outpatient and inpatient stroke clinics between Mar. 1, 2007, and Aug. 31, 2009. Nearly half (45%, 170) of the participants had some disability due to stroke. Participants were visited at home for a baseline assessment and randomly allocated to home blood pressure monitoring (n = 187) or usual care (n = 194). Those in the intervention group were given a monitor, brief training and telephone support. Participants who had home blood pressure readings consistently over target (target < 130/80 mm Hg) were advised to consult their family physician. The main outcome measure was a fall in systolic blood pressure after 12 months, measured by an independent researcher unaware of group allocation. RESULTS: Despite more patients in the intervention group than in the control group having changes to antihypertensive treatment during the trial period (60.1% [98/163] v. 47.6% [78/164], p = 0.02), the fall in systolic blood pressure from baseline did not differ significantly between the groups (adjusted mean difference 0.3 mm Hg, 95% confidence interval -3.6 to 4.2 mm Hg). Subgroup analysis showed significant interaction with disability due to stroke (p = 0.03 at 6 months) and baseline blood pressure (p = 0.03 at 12 months). INTERPRETATION: Overall, home monitoring did not improve blood pressure control in patients with hypertension and a history of stroke. It was associated with a fall in systolic pressure in patients who had uncontrolled blood pressure at baseline and those without disability due to stroke. TRIAL REGISTRATION: ClinicalTrials.gov registration NCT00514800.

Evidence for empagliflozin in heart failure with preserved ejection fraction (HFpEF).

Commentary on: Anker SD, Butler J, Filippatos G, et al Empagliflozin in heart failure with a preserved ejection fraction. New England Journal of Medicine, 2021; 385:1451-61.

Dapagliflozin in people with chronic kidney disease.

Commentary on: Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-46. Series Editor: Dr Teck Khong, DTB Associate Editor, Clinical Pharmacology, St George's, University of London, UK.

Is alternate day dosing of oral iron an effective option for iron-deficiency anaemia?

Commentary on: Kaundal R, Bhatia P, Jain A, et al. Randomized controlled trial of twice-daily versus alternate-day oral iron therapy in the treatment of iron-deficiency anemia. Ann Hematol. 2020;99:57-63. Series Editor: Dr Teck Khong, DTB Associate Editor, Clinical Pharmacology, St George's, University of London, UK.

What does the TIME study tell us about morning and evening dosing of antihypertensive medication?

Commentary on: Mackenzie IS, Rogers A, Poulter NR, et al Cardiovascular outcomes in adults with hypertension with evening vs morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial. Lancet 2022;400:1417-25.

Resident phenotypically modulated vascular smooth muscle cells in healthy human arteries.

Vascular interstitial cells (VICs) are non-contractile cells with filopodia previously described in healthy blood vessels of rodents and their function remains unknown. The objective of this study was to identify VICs in human arteries and to ascertain their role. VICs were identified in the wall of human gastro-omental arteries using transmission electron microscopy. Isolated VICs showed ability to form new and elongate existing filopodia and actively change body shape. Most importantly sprouting VICs were also observed in cell dispersal. RT-PCR performed on separately collected contractile vascular smooth muscle cells (VSMCs) and VICs showed that both cell types expressed the gene for smooth muscle myosin heavy chain (SM-MHC). Immunofluorescent labelling showed that both VSMCs and VICs had similar fluorescence for SM-MHC and αSM-actin, VICs, however, had significantly lower fluorescence for smoothelin, myosin light chain kinase, h-calponin and SM22α. It was also found that VICs do not have cytoskeleton as rigid as in contractile VSMCs. VICs express number of VSMC-specific proteins and display features of phenotypically modulated VSMCs with increased migratory abilities. VICs, therefore represent resident phenotypically modulated VSMCs that are present in human arteries under normal physiological conditions.

Short-term effect of deprescribing antihypertensives in older people.

Commentary on: Sheppard JP, Burt J, Lown M, et al Effect of antihypertensive medication reduction vs usual care on short-term blood pressure control in patients with hypertension aged 80 years and older: The OPTIMISE randomized clinical trial. JAMA 2020;323:2039-51.Series co-ordinator: Dr Teck Khong, DTB Associate Editor, Clinical Pharmacology, St George's, University of London, UK.

Treating hypertension with a pill containing very low doses of four antihypertensive agents compared with standard dose irbesartan.

Commentary on: Chow CK, Atkins ER, Hillis GS, et al Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial. Lancet 2021;398:1043-52. Series co-ordinator: Dr Teck Khong, DTB Associate Editor Clinical Pharmacology, St George's, University of London, UK.

What role for PCI in stable ischaemic heart disease?

Commentary on: Maron DJ, Hochman JS, Reynolds HR, et al Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med 2020;382:1395-1407.Series co-ordinator: Dr Teck Khong, DTB Associate Editor Clinical Pharmacology, St George's, University of London, UK.

Effect of PCI of culprit and non-culprit lesions for patients with STEMI compared with culprit lesion-only PCI.

Commentary on: Mehta SR, Wood DA, Storey RF, et al Complete Revascularization with Multivessel PCI for Myocardial Infarction. N Engl J Med 2019; 381:1411-21. Commentary by: Dr Emma Magavern and Dr Teck Khong Clinical Pharmacology, St George's, University of London, UK. Series Editor: Dr Teck Khong, DTB Associate Editor Clinical Pharmacology, St George's, University of London, UK.

Effect of dapagliflozin on cardiovascular events in patients with type 2 diabetes.

Commentary on: Wiviott SD, Raz I, Bonaca MP, et al Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57. Commentary by: Dr Emma Magavern and Dr Teck Khong Clinical Pharmacology, St George's, University of London, UK Series Editor: Dr Teck Khong, DTB Associate Editor Clinical Pharmacology, St George's, University of London, UK.

Effect of dapagliflozin in patients with heart failure.

Commentary on: McMurray JJV, Solomon SD, Inzucchi SE, et al Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008. Commentary by: Dr Joshua Au Yeunga, Clinical Pharmacology, St Thomas' Hospital, London, UK and Dr Teck Khong, Clinical Pharmacology, St George's, University of London, UK. Series Editor: Dr Teck Khong, DTB Associate Editor, Clinical Pharmacology, St George's, University of London, UK.

Moderate calorie restriction improves cardiometabolic risk factors in healthy individuals.

Commentary by: Dr James Kimpton and Dr Teck Khong Clinical Pharmacology, St George's, University of London, UKSeries Editor: Dr Teck Khong, DTB Associate Editor Clinical Pharmacology, St George's, University of London, UKCommentary on: Kraus WE, Bhapkar M, Huffman KM, et al 2 years of calorie restriction and cardiometabolic (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinol 2019; 7: 673-83.

Is tramadol associated with an increase in all-cause mortality among patients with osteoarthritis?

Commentary on: Zeng C, Dubreuil M, LaRochelle MR, et al Association of tramadol with all-cause mortality among patients with osteoarthritis. JAMA 2019;321:969-82 Commentary by: Dr Catrin Page and Dr Teck Khong Clinical Pharmacology, St George's, University of London, UK Series Editor: Dr Teck Khong, DTB Associate Editor Clinical Pharmacology, St George's, University of London, London, UK.

No benefit from amitriptyline for chronic low back pain?

DTB commentaries provide an overview of, and commentary on, a clinical trial, systematic review or observational study.

Prescribing of anticholinergic medicines to patients initiating dementia medicines.

Commentary on: Narayan SW, Pearson SA, Litchfield M, et al Anticholinergic medicines use among older adults before and after initiating dementia medicines. BJCP 2019;85:1957-1963.Commentary by: Dr Christopher JD Threapleton and Dr Teck Khong, Clinical Pharmacology, St George's, University of London, UKSeries Editor: Dr Teck Khong, DTB Associate Editor, Clinical Pharmacology, St George's, University of London, London, UK.