Endovascular ultrasound renal denervation to lower blood pressure in young hypertensive women planning pregnancy: study protocol for a multicentre randomised, blinded and sham controlled proof of concept study.

INTRODUCTION: A major issue confronting clinicians treating hypertension in pregnancy is the limited number of pharmacological options. Endovascular catheter-based renal denervation (RDN) is a new method to lower blood pressure (BP) in patients with hypertension by reducing the activity of the renal sympathetic nervous system. Drugs that affect this system are safe in pregnant women. So there is reasonable evidence that RDN performed before pregnancy should not have deleterious effects for the fetus. Because the efficacy of RDN may be greater in younger patients and in women, we may expect a larger proportion of BP normalisation in young hypertensive women, but this remains to be proven. Our primary objective is to quantify the proportion of BP normalisation with RDN in this population. METHODS AND ANALYSIS: WHY-RDN is a multicentre randomised sham-controlled trial conducted in six French hypertension centres that will include 80 women with essential hypertension treated or untreated, who are planning a pregnancy in the next 2 years and will be randomly assigned to RDN or classic renal arteriography and sham RDN in a ratio of 1:1. The primary outcome is the normalisation of 24-hour BP (<130/80 mm Hg) at 2-month post procedure off treatment. Sample size is calculated with the following assumptions: 5% one-sided significance level (α), 80% power (1-ß), expected responder rates of 24% and 3% in the treatment and control group, respectively. Secondary outcomes include the absence of adverse outcomes for a future pregnancy, the variations of BP in ambulatory and home BP measurements and the evaluation of treatment prescribed. ETHICS AND DISSEMINATION: WHY-RDN has been approved by the French Ethics Committee (Tours, Region Centre, Ouest 1- number 2021T1-28 HPS). This project is being carried out in accordance with national and international guidelines. The findings of this study will be disseminated by publication. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT05563337.

Cardiovascular and health cost impacts of cuff blood pressure underestimation and overestimation of invasive aortic systolic blood pressure.

OBJECTIVE: Hypertension management is directed by cuff blood pressure (BP), but this may be inaccurate, potentially influencing cardiovascular disease (CVD) events and health costs. This study aimed to determine the impact on CVD events and related costs of the differences between cuff and invasive SBP. METHODS: Microsimulations based on Markov modelling over one year were used to determine the differences in the number of CVD events (myocardial infarction or coronary death, stroke, atrial fibrillation or heart failure) predicted by Framingham risk and total CVD health costs based on cuff SBP compared with invasive (aortic) SBP. Modelling was based on international consortium data from 1678 participants undergoing cardiac catheterization and 30 separate studies. Cuff underestimation and overestimation were defined as cuff SBP less than invasive SBP and cuff SBP greater than invasive SBP, respectively. RESULTS: The proportion of people with cuff SBP underestimation versus overestimation progressively increased as SBP increased. This reached a maximum ratio of 16 : 1 in people with hypertension grades II and III. Both the number of CVD events missed (predominantly stroke, coronary death and myocardial infarction) and associated health costs increased stepwise across levels of SBP control, as cuff SBP underestimation increased. The maximum number of CVD events potentially missed (11.8/1000 patients) and highest costs ($241 300 USD/1000 patients) were seen in people with hypertension grades II and III and with at least 15 mmHg of cuff SBP underestimation. CONCLUSION: Cuff SBP underestimation can result in potentially preventable CVD events being missed and major increases in health costs. These issues could be remedied with improved cuff SBP accuracy.

How to measure arterial stiffness independently of blood pressure: the QKD method.

OBJECTIVE: Arterial stiffness, an important predictor of cardiovascular event, has two components: one linked to the nonlinear elastic behaviour of the arterial wall and dependent of the blood pressure (BP) at the time of measurement, and the other linked to the structural modifications of the arterial wall as the consequences of the long-term effects of all cardiovascular risk factors, including BP. This second component is certainly the most important one and can be assessed with 24-h ambulatory monitoring of cardio-arm pulse transmission time (QKD method). METHODS: The working hypothesis of this study is that QKD100-60, the value of the QKD for a 100 mmHg SBP and 60 bpm heart rate is independent of 24-h SBP in both normotensive volunteers and treated hypertensive patients, in whom the long-term influence of BP is limited, whereas QKD100-60 is not independent of 24-h SBP in untreated hypertensive patients in whom high BP was able to damage the arterial wall on the long term. So we studied the relationships of QKD100-60 with 24-h BP and heart rate together with age, sex, height in multivariate regression analysis in three groups of patients; normal, untreated and treated hypertensive patients. QKD was measured with Novacor devices. RESULTS: In the normal population (n = 323, aged 29 ±â€Š10 years) and in the treated hypertensive population (n = 425, aged 58 ±â€Š13 years) the QKD100-60 was indeed not significantly related to 24-h SBP. In the untreated hypertensive population (n = 614, aged 51 ±â€Š13 years) the QKD100-60 was weakly but significantly related to 24-h SBP (r = 0.249, P < 0.0001). CONCLUSION: Ambulatory monitoring of QKD provides indices of arterial stiffness independent of BP level at the time of measurement and most interestingly of 24-h BP with the potential to refine risk in patients with low traditional risk scores.

Revisiting malignant hypertension: rationale and design of the 'HAMA cohort', on behalf of the ESH working group 'hypertension and the kidney'.

BACKGROUND: Malignant hypertension has not disappeared and is associated with a poor prognosis. Yet, so far, it has received limited attention from the medical community. Guidelines are mainly based on expert consensus and low quality evidences. METHOD: We set up a prospective, multicenter, observational cohort of patients with malignant hypertension. We collect at admission medical history, demographic data, ongoing treatment, clinical parameters, symptoms, care pathways, target organ status and at discharge and during follow up treatment administrated, adverse events, blood pressure level, target organ status. We aim to recruit 500 patients with malignant hypertension in 5 years, with a 5-year follow-up. Our primary objective is to assess the 5 years prognosis of these patients. DISCUSSION: The HAMA (Hypertension Arterielle MAligne, meaning malignant hypertension) registry aims to describe the epidemiology and to assess the prognosis of malignant hypertension in a contemporary multidisciplinary cohort, with emphasis on the diversity of current management and care pathway among the different medical specialties. It may help improving our pathophysiological knowledge, and pave the way to update the definition of this particular form of hypertension. The multidisciplinary network developed in the wake of this project is expected to facilitate the set up therapeutic trials, laying the ground for evidence-based recommendations.

Arterial stiffness (from monitoring of Qkd interval) predict the occurrence of cardiovascular events and total mortality.

Arterial stiffness, most often assessed with carotido-femoral pulse wave velocity predicts cardiovascular events but its use in clinical practice remains limited. The 24 h ambulatory monitoring of Blood pressure and timing of Korotkoff sounds (QKD interval) allows an automatic assessment of arterial stiffness and is an independent predictor of cardiovascular events in hypertensive patients. The long term follow up of our cohort of hypertensive patients gave us the opportunity to test the consequences of increased arterial stiffness on the incidence of all causes deaths and to define the populations who could benefit of this measurement beyond risk scores. The sample includes 930 patients (502 males, age 53 ± 13 years, baseline risk SCORE2-OP = 6.70 ± 4.97%) with an average follow up of 12.11 ± 7.4 years (0.3-30). In this population 169 cardiovascular events and 155 deaths were recorded. SCORE2-OP, 24 h Systolic Blood Pressure and arterial stiffness (QKDh) as a continuous or discontinuous variable (normal or reduced) were significantly and independently linked to the occurrence of cardiovascular events or all cause deaths in multivariate Cox model. ROC curves analysis show that measuring arterial stiffness with QKD method offers the best predictive value in patients with low or very low risk scores.

Cost Analysis of Radiofrequency Ablation for Adrenal Adenoma in Patients with Primary Aldosteronism and Hypertension: Results from the ADERADHTA Pilot Study and Comparison with Surgical Adrenalectomy.

PURPOSE: Primary Aldosteronism (PA) is increasingly considered as a common disease affecting up to 10% of the hypertensive population. Standard of care comprises laparoscopic total adrenalectomy but innovative treatment such as RadioFrequency Ablation (RFA) constitutes an emerging promising alternative to surgery. The main aim of this study is to analyse the cost of RFA versus surgery on aldosterone-producing adenoma patient from the French National Health Insurance (FNHI) perspective. METHODS: The ADERADHTA study was a prospective pilot study aiming to evaluate both safety and efficacy of the novel use of adrenal RFA on the patients with PA. This study conducted on two French sites and enrolled adult patients, between 2016 and 2018, presenting hypertension and underwent the RFA procedure. Direct medical (inpatient and outpatient) and non-medical (transportation, daily allowance) costs were calculated over a 6-month follow-up period. Moreover, the procedure costs for the RFA were calculated from the hospital perspective. Descriptive statistics were implemented. RESULTS: Analysis was done on 21 patients in RFA groups and 27 patients in the surgery group. The difference in hospital costs between the RFA and surgery groups was €3774 (RFA: €1923; Surgery: €5697 p < 0.001) in favour of RFA. Inpatient and outpatient costs over the 6-month follow-up period were estimated at €3,48 for patients who underwent RFA. The production cost of implementing the RFA procedure was estimated at €1539 from the hospital perspective. CONCLUSION: Our study was the first to show that RFA is 2 to 3 times less costly than surgery. The trial is registered at ClinicalTrials.gov under the number NCT02756754.

Sex Differences in Blood Pressure and Potential Implications for Cardiovascular Risk Management.

BACKGROUND: Accurate blood pressure (BP) measurement is critical for optimal cardiovascular risk management. Age-related trajectories for cuff-measured BP accelerate faster in women compared with men, but whether cuff BP represents the intraarterial (invasive) aortic BP is unknown. This study aimed to determine the sex differences between cuff BP, invasive aortic BP, and the difference between the 2 measurements. METHODS: Upper-arm cuff BP and invasive aortic BP were measured during coronary angiography in 1615 subjects from the Invasive Blood Pressure Consortium Database. This analysis comprised 22 different cuff BP devices from 28 studies. RESULTS: Subjects were 64±11 years (range 40-89) and 32% women. For the same cuff systolic BP (SBP), invasive aortic SBP was 4.4 mm Hg higher in women compared with men. Cuff and invasive aortic SBP were higher in women compared with men, but the sex difference was more pronounced from invasive aortic SBP, was the lowest in younger ages, and the highest in older ages. Cuff diastolic blood pressure overestimated invasive diastolic blood pressure in both sexes. For cuff and invasive diastolic blood pressure separately, there were sex*age interactions in which diastolic blood pressure was higher in younger men and lower in older men, compared with women. Cuff pulse pressure underestimated invasive aortic pulse pressure in excess of 10 mm Hg for both sexes in older age. CONCLUSIONS: For the same cuff SBP, invasive aortic SBP was higher in women compared with men. How this translates to cardiovascular risk prediction needs to be determined, but women may be at higher BP-related risk than estimated by cuff measurements.

Renin-Angiotensin System Inhibitors in Patients With COVID-19: A Meta-Analysis of Randomized Controlled Trials Led by the International Society of Hypertension.

Background Published randomized controlled trials are underpowered for binary clinical end points to assess the safety and efficacy of renin-angiotensin system inhibitors (RASi) in adults with COVID-19. We therefore performed a meta-analysis to assess the safety and efficacy of RASi in adults with COVID-19. Methods and Results MEDLINE, EMBASE, ClinicalTrials.gov, and the Cochrane Controlled Trial Register were searched for randomized controlled trials that randomly assigned patients with COVID-19 to RASi continuation/commencement versus no RASi therapy. The primary outcome was all-cause mortality at ≤30 days. A total of 14 randomized controlled trials met the inclusion criteria and enrolled 1838 participants (aged 59 years, 58% men, mean follow-up 26 days). Of the trials, 11 contributed data. We found no effect of RASi versus control on all-cause mortality (7.2% versus 7.5%; relative risk [RR], 0.95; [95% CI, 0.69-1.30]) either overall or in subgroups defined by COVID-19 severity or trial type. Network meta-analysis identified no difference between angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers. RASi users had a nonsignificant reduction in acute myocardial infarction (2.1% versus 3.6%; RR, 0.59; [95% CI, 0.33-1.06]), but increased risk of acute kidney injury (7.0% versus 3.6%; RR, 1.82; [95% CI, 1.05-3.16]), in trials that initiated and continued RASi. There was no increase in need for dialysis or differences in congestive cardiac failure, cerebrovascular events, venous thromboembolism, hospitalization, intensive care admission, inotropes, or mechanical ventilation. Conclusions This meta-analysis of randomized controlled trials evaluating angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers versus control in patients with COVID-19 found no difference in all-cause mortality, a borderline decrease in myocardial infarction, and an increased risk of acute kidney injury with RASi. Our findings provide strong evidence that RASi can be used safely in patients with COVID-19.

Adrenal BORDeAux reGistry: Bordeaux single-center study of hypertensive patients with primary hyperaldosteronism.

BACKGROUND: Primary aldosteronism is responsible for a major cardiovascular risk that can be avoided by specific treatment. A better characterization of the hypertensive population with primary aldosteronism would not only improve the overall diagnosis but also allows a better selection of patients requiring adrenal vein sampling (AVS). METHODS: Creation of a prospective single-center Bordeaux ABORDAGE study of hypertensive patients with primary aldosteronism who underwent AVS. Primary aldosteronism was diagnosed according to the recommendations of the SFE/SFHTA. Peripheral and central blood pressure measurements were performed with mercury sphygmomanometer, SphygmoCor applanation tonometer and ambulatory blood pressure measurement. An adrenal computed tomography and an unstimulated AVS were performed in each patient. RESULTS: One hundred and eighty-eight patients were included in our study. They were mostly men (61.7%), with a mean age of 48.7 ±â€Š10.5 years, BMI of 29.7 ±â€Š5 kg/ m2 and duration of hypertension of 101.5 ±â€Š84 months. AVS was selective in 82.3% of patients and lateralization was concordant with CT in only 35.4% of patients. Lateralized secretion was significantly associated with a marked biological primary aldosteronism and hypertension. In multivariate analysis, no variable specifically differentiated patients with aldosterone lateralization. CONCLUSION: The ABORDAGE population description is consistent with the data found in the literature. These characteristics are ultimately those expected in essential hypertension population, which therefore, could explain part of the underdiagnosis of primary aldosteronism. Only AVS is able to predict the lateralization of secretion with a post adrenalectomy recovery of about 90% in case of lateralization. The generalization of AVS would, therefore, increase the proportion of patients with primary aldosteronism cured.

Long-term evolution of ambulatory blood pressure and cardiovascular events in hypertensive patients.

Ambulatory blood pressure monitoring (ABPM) is now considered the gold standard to evaluate BP, and predicts related cardiovascular risk. However, no study has reported the association of long-term changes in ABPM with the incidence of cardiovascular events, therefore the objective of this work. We included patients from the Bordeaux cohort of hypertensive patients, who had undergone at least two ABPM; the first was performed before or after antihypertensive treatment was started, and the second was the last recording available before any cardiovascular event. We included 591 patients (mean age, 54 years) with a 7-year average interval between the first and last ABPM, a 10-year average follow-up, and a total of 111 cardiovascular events. The patients were divided into four groups: G0, first and last 24 h systolic blood pressure (SBP) < 130; G1, first 24 h SBP ≥ 130, last 24 h SBP < 130; G2, first 24 h SBP < 130, last 24 h SBP ≥ 130; and G3, first 24 h SBP ≥ 130, last 24 h SBP ≥ 130 mmHg. Baseline ABPM better predicted future events than the last ABPM. G0 and G2 had similar survival. G1 and G3 had a worse prognosis than G0 and G2, while G1 had an intermediate risk between G0 and G3, indicating some benefit of treatment. In conclusion, our study showed the prognostic value of the first ABPM recorded in hypertensive patients and the persistence of risk when 24 h BP is controlled by antihypertensive treatment.

Neurologically asymptomatic patients frequently present cerebral injuries during malignant hypertension: a MRI study.

BACKGROUND: Acute and diffuse microvascular damage characterizes malignant hypertension (MHT), the deadliest form of hypertension (HTN). Although its ophthalmological, renal and cardiological repercussions are well known, brain involvement is considered rare with few descriptions, although it is one of the main causes of death. We hypothesized that brain MRI abnormalities are common in MHT, even in patients without objective neurological signs. METHOD: We analyzed retrospectively the brain MRI of patients admitted for acute MHT between 2008 and 2018 in Bordeaux University Hospital, regardless of their neurological status. A trained operator analyzed every brain MRI, looking for posterior reversible encephalopathy syndrome (PRES), ischemic stroke, intracerebral hematoma (ICH) and microangiopathy markers. We included 58 patients without neurological signs, 66% were men, and mean age was 45.6 ±â€Š11.3 years. RESULTS: Brain MRI were normal in 26% of patients but we found at least one acute abnormality on brain MRI in 29% and an Small Vessel Disease score (SVD score) of two or higher in 52%. In patients with neurological signs, these findings were 9, 53 and 70%, respectively. A PRES was found in 16% of asymptomatic patients and 31% had an ischemic stroke and/or a cerebral hematoma. CONCLUSION: PRES, recent hematoma, ischemic stroke and severe cerebral microangiopathy are common findings in MHT patients without neurological signs on admission. The impact of these findings on patient management, and their cerebrovascular and cognitive prognostic value, should be established. Brain MRI might need to become systematic in patients suffering from MHT episodes.

Short-term blood pressure variability, arterial stiffness, and cardiovascular events: results from the Bordeaux cohort.

OBJECTIVE: Short-term blood pressure variability derived from 24-h ambulatory monitoring is associated with poor cardiovascular prognosis. However, previous analyses of this have clearly been influenced by clinical cofounders, particularly blood pressure (BP) level. Arterial stiffness is a powerful marker of cardiovascular risk, which may influence BP variability. In this study, we assessed the prognostic value of BP variability based on 24-h ambulatory measurements and adjusted for arterial stiffness. METHODS: Population: Bordeaux cohort of hypertensive patients. Inclusion criteria were 24-h ambulatory BP monitoring at baseline with measurements every 15' day and night, determination of wake-up time and bedtime, and assessment of arterial stiffness with monitoring of Korotkoff sound arrival time. A total of 969 patients (age 54 ±â€Š14 years) with an average follow up of 120 ±â€Š78 months and 178 cardiovascular recorded events were included. RESULTS: In univariate survival analyses, the standard deviations of day, night, and 24-h SBP were associated with the occurrence of cardiovascular events. The standard deviation of night-time SBP showed the strongest association with the outcome variable and was entered into multivariate analyses. In multivariate analyses, night-time SBP variability remained significantly associated with the occurrence of cardiovascular events after adjusting for major cardiovascular risk factors, 24-h SBP, and arterial stiffness. BP variability and arterial stiffness showed no significant association. CONCLUSION: Our results suggest that variability of night-time SBP is an important marker of the risk of cardiovascular events in hypertensive patients, independently of average 24-h BP and arterial stiffness.

Identifying Isolated Systolic Hypertension From Upper-Arm Cuff Blood Pressure Compared With Invasive Measurements.

Isolated systolic hypertension (ISH) is the most common form of hypertension and is highly prevalent in older people. We recently showed differences between upper-arm cuff and invasive blood pressure (BP) become greater with increasing age, which could influence correct identification of ISH. This study sought to determine the difference between identification of ISH by cuff BP compared with invasive BP. Cuff BP and invasive aortic BP were measured in 1695 subjects (median 64 years, interquartile range [55-72], 68% male) from the INSPECT (Invasive Blood Pressure Consortium) database. Data were recorded during coronary angiography among 29 studies, using 21 different cuff BP devices. ISH was defined as ≥130/<80 mm Hg using cuff BP compared with invasive aortic BP as the reference. The prevalence of ISH was 24% (n=407) according to cuff BP but 38% (n=642) according to invasive aortic BP. There was fair agreement (Cohen κ, 0.36) and 72% concordance between cuff and invasive aortic BP for identifying ISH. Among the 28% of subjects (n=471) with misclassification of ISH status by cuff BP, 20% (n=96) of the difference was due to lower cuff systolic BP compared with invasive aortic systolic BP (mean, -16.4 mm Hg [95% CI, -18.7 to -14.1]), whereas 49% (n=231) was from higher cuff diastolic BP compared with invasive aortic diastolic BP (+14.2 mm Hg [95% CI, 11.5-16.9]). In conclusion, compared with invasive BP, cuff BP fails to identify ISH in a sizeable portion of older people and demonstrates the need to improve cuff BP measurements.

Ambulatory Blood Pressure Monitoring to Predict Response to Renal Denervation: A Post Hoc Analysis of the RADIANCE-HTN SOLO Study.

Renal denervation (RDN) is effective in lowering blood pressure (BP) in patients with hypertension. The issue remains how to best identify potential responders. Ambulatory BP monitoring may be useful. Baseline nighttime systolic BP (SBP) ≥136 mm Hg and its variability (SD) ≥12 mm Hg in DENER-HTN trial or 24-hour heart rate ≥73.5 bpm in SPYRAL HTN-OFF MED Trial were shown to predict the BP response to RDN. We applied these criteria to the patients with hypertension in the sham-controlled RADIANCE-HTN SOLO trial to predict the BP response to ultrasound RDN at 2 months while patients were maintained off medications. BP responders were defined as: clinical with 24-hour SBP <130 mm Hg (RDN: 22/64 versus sham: 7/58); meaningful with 24-hour SBP reduction ≥10 mm Hg (RDN: 24/64, sham: 7/58); and extreme with 24-hour SBP reduction above mean+2 SD of the SBP decrease in the sham group, that is, ≥16.5 mm Hg (RDN: 10/64 versus sham: 2/58). The predictive criteria reported above were tested for sensitivity, specificity, and positive and negative predictive values. The predictive value varied according to the definition of response, with the clinical definition being strongly influenced by regression to the mean. Baseline nighttime SBP and its variability, especially when combined, offered good specificity (>90% irrespective of definition) but low sensitivity (from 9.1% to 30% depending on the definition) to predict responders; the heart rate criterion had insufficient predictive value. This analysis suggests the potential role of nighttime SBP and its variability to predict BP response to RDN in patients with hypertension. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02649426.

Radiofrequency ablation for adenoma in patients with primary aldosteronism and hypertension: ADERADHTA, a pilot study.

OBJECTIVE: To evaluate the efficacy and the feasibility of radiofrequency ablation to treat aldosterone-producing adenomas. METHODS: In an open prospective bicentric pilot study, patients with hypertension on ambulatory blood pressure measurement, a primary aldosteronism, an adenoma measuring less than 4 cm, and confirmation of lateralization by adrenal venous sampling were recruited. The primary endpoint, based on ABPM performed at 6 months after the radiofrequency ablation, was a daytime SBP/DBP less than 135/85 mmHg without any antihypertensive drugs or a reduction of at least 20 mmHg for SBP or 10 mmHg for DBP. RESULTS: Thirty patients have been included (mean age = 51 ±â€Š11 years; 50% women). Mean baseline daytime SBP and DBP were 144 ±â€Š19 / 95 ±â€Š15 mmHg and 80% received at least two antihypertensive drugs. At 6 months: 47% (95% CI 28-66) of patients reached the primary endpoint, mean daytime SBP and DBP were 131 ±â€Š14 (101-154)/87 ±â€Š10 (71-107) mmHg; 43% of them did not take any antihypertensive drug and 70% of them did not take potassium supplements. Few complications were recorded: four cases of back pain at day 1 postablation; three limited pneumothoraxes, which resolved spontaneously; one lesion of a polar renal artery. CONCLUSION: Radiofrequency ablation for hypertensive patients with aldosterone-producing adenomas seems to be an emerging promising alternative to surgery. Its efficacy and its feasibility have to be confirmed in a larger sample of patients.

Home Treatment of Older People with Symptomatic SARS-CoV-2 Infection (COVID-19): A structured Summary of a Study Protocol for a Multi-Arm Multi-Stage (MAMS) Randomized Trial to Evaluate the Efficacy and Tolerability of Several Experimental Treatments to Reduce the Risk of Hospitalisation or Death in outpatients aged 65 years or older (COVERAGE trial).

OBJECTIVES: To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation. TRIAL DESIGN: Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial. PARTICIPANTS: Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate <50/min; Kalaemia >5.5 mmol/L or <3.5 mmol/L; Ongoing treatment with piperaquine, halofantrine, dasatinib, nilotinib, hydroxyzine, domperidone, citalopram, escitalopram, potent inhibitors or inducers of cytochrome P450 CYP3A4 isoenzyme, repaglinide, azathioprine, 6-mercaptopurine, theophylline, pyrazinamide, warfarin; Known hypersensitivity to any of the trial drugs or to chloroquine and other 4-aminoquinolines, amodiaquine, mefloquine, glafenine, floctafenine, antrafenine, ARB; Hepatic porphyria; Liver failure (Child-Pugh stage ≥B); Stage 4 or 5 chronic kidney disease (GFR <30 mL/min/1.73 m²); Dialysis; Hypersentivity to lactose; Lactase deficiency; Abnormalities in galactose metabolism; Malabsorption syndrome; Glucose-6-phosphate dehydrogenase deficiency; Symptomatic hyperuricemia; Ileus; Colitis; Enterocolitis; Chronic hepatitis B virus disease. The trial is being conducted in France in the Bordeaux, Corse, Dijon, Nancy, Paris and Toulouse areas as well as in the Grand Duchy of Luxembourg. Participants are recruited either at home, nursing homes, general practices, primary care centres or hospital outpatient consultations. INTERVENTION AND COMPARATOR: The four experimental treatments planned in protocol version 1.2 (April 8th, 2020) are: (1) Hydroxychloroquine 200 mg, 2 tablets BID on day 0, 2 tablets QD from day 1 to 9; (2) Imatinib 400 mg, 1 tablet QD from day 0 to 9; (3) Favipiravir 200 mg, 12 tablets BID on day 0, 6 tablets BID from day 1 to 9; (4) Telmisartan 20 mg, 1 tablet QD from day 0 to 9. The comparator is a complex of vitamins and trace elements (AZINC Forme et Vitalité®), 1 capsule BID for 10 days, for which there is no reason to believe that they are active on the virus. In protocol version 1.2 (April 8th, 2020): People in the control arm will receive a combination of vitamins and trace elements; people in the experimental arms will receive hydroxychloroquine, or favipiravir, or imatinib, or telmisartan. MAIN OUTCOME: The primary outcome is the proportion of participants with an incidence of hospitalisation and/or death between inclusion and day 14 in each arm. RANDOMISATION: Participants are randomized in a 1:1:1:1:1 ratio to each arm using a web-based randomisation tool. Participants not treated with an ARB or ACEI prior to enrolment are randomized to receive the comparator or one of the four experimental drugs. Participants already treated with an ARB or ACEI are randomized to receive the comparator or one of the experimental drugs except telmisartan (i.e.: hydroxychloroquine, imatinib, or favipiravir). Randomisation is stratified on ACEI or ARBs treatment at inclusion and on the type of residence (personal home vs. nursing home). BLINDING (MASKING): This is an open-label trial. Participants, caregivers, investigators and statisticians are not blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 1057 participants will be enrolled if all arms are maintained until the final analysis and no additional arm is added. Three successive futility interim analyses are planned, when the number of participants reaches 30, 60 and 102 in the control arm. Two efficacy analyses (interim n°3 and final) will be performed successively. TRIAL STATUS: This describes the Version 1.2 (April 8th, 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15th, 2020 in the Nouvelle Aquitaine region (South-West France). Given the current decline of the COVID-19 pandemic in France and its unforeseeable dynamic in the coming months, new trial sites in 5 other French regions and in Luxembourg are currently being opened. A revised version of the protocol was submitted to the regulatory authority and ethics committee on June 15th, 2020. It contains the following amendments: (i) Inclusion criteria: age ≥65 replaced by age ≥60; time since first symptoms <3 days replaced by time since first symptoms <5 days; (ii) Withdrawal of the hydroxychloroquine arm (due to external data); (iii) increase in the number of trial sites. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on April 22nd, 2020 (Identifier: NCT04356495): and on EudraCT on April 10th, 2020 (Identifier: 2020-001435-27). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

The pharmacological management of malignant hypertension.

: Malignant hypertension (MHT) still remains a severe condition that requires early recognition and treatment. Over the years, the prevention and treatment of MHT have significantly advanced through the introduction of modern antihypertensive agents. However, in the absence of robust clinical trials, there remain no formal guidelines on the treatment of MHT. This review summarizes the historical background and pathophysiological evidence of MHT, which has led to common practices in its pharmacological management but can also introduce challenges. The current consensus for treatment involves early intravenous infusion of antihypertensive agents, but oral blockers of the renin-angiotensin system may improve the management of MHT, and it offers a suitable treatment option in low-income countries where the condition remains relatively prevalent.