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The New England Journal of Medicine Jul 2023Angiotensinogen is the sole precursor of angiotensin peptides and has a key role in the pathogenesis of hypertension. Zilebesiran, an investigational RNA interference... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Angiotensinogen is the sole precursor of angiotensin peptides and has a key role in the pathogenesis of hypertension. Zilebesiran, an investigational RNA interference therapeutic agent with a prolonged duration of action, inhibits hepatic angiotensinogen synthesis.
METHODS
In this phase 1 study, patients with hypertension were randomly assigned in a 2:1 ratio to receive either a single ascending subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo and were followed for 24 weeks (Part A). Part B assessed the effect of the 800-mg dose of zilebesiran on blood pressure under low- or high-salt diet conditions, and Part E the effect of that dose when coadministered with irbesartan. End points included safety, pharmacokinetic and pharmacodynamic characteristics, and the change from baseline in systolic and diastolic blood pressure, as measured by 24-hour ambulatory blood-pressure monitoring.
RESULTS
Of 107 patients enrolled, 5 had mild, transient injection-site reactions. There were no reports of hypotension, hyperkalemia, or worsening of renal function resulting in medical intervention. In Part A, patients receiving zilebesiran had decreases in serum angiotensinogen levels that were correlated with the administered dose (r = -0.56 at week 8; 95% confidence interval, -0.69 to -0.39). Single doses of zilebesiran (≥200 mg) were associated with decreases in systolic blood pressure (>10 mm Hg) and diastolic blood pressure (>5 mm Hg) by week 8; these changes were consistent throughout the diurnal cycle and were sustained at 24 weeks. Results from Parts B and E were consistent with attenuation of the effect on blood pressure by a high-salt diet and with an augmented effect through coadministration with irbesartan, respectively.
CONCLUSIONS
Dose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory blood pressure were sustained for up to 24 weeks after a single subcutaneous dose of zilebesiran of 200 mg or more; mild injection-site reactions were observed. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT03934307; EudraCT number, 2019-000129-39.).
Topics: Humans; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Double-Blind Method; Hypertension; Irbesartan; RNA Interference; Tetrazoles; Diet; Injections, Subcutaneous
PubMed: 37467498
DOI: 10.1056/NEJMoa2208391 -
Current Opinion in Cardiology Jul 2023Hypertensive crisis (HTN-C) is a condition of increasing prevalence. It carries significant morbidity and mortality, and prompt recognition and treatment are crucial.... (Review)
Review
PURPOSE OF REVIEW
Hypertensive crisis (HTN-C) is a condition of increasing prevalence. It carries significant morbidity and mortality, and prompt recognition and treatment are crucial. There is a paucity of controlled trials, so a working knowledge of the most recent literature in the area of HTN-C is helpful.
RECENT FINDINGS
Novel serological markers, including serum corin, have been found to aid in the early identification of end-organ damage from severely elevated blood pressure (BP). In the area of BP following thrombolysis for ischemic stroke, lower target BP (130-140 mmHg) is associated with some improved outcomes. Two large trials of lower BP following mechanical thrombectomy in stroke have failed to show improved outcomes; however, observed data show benefits at lower than currently recommended levels. Clevidipine, a calcium channel blocker marketed for unique use in HTN-C, was found to be noninferior to the generic less expensive nicardipine. Oral nifedipine was found to be the most effective agent for sustained BP reduction in preeclampsia.
SUMMARY
HTN-C remains an area with few prospective randomized trials, but there is active research on identifying lower goals for specific clinical scenarios. Ideal therapeutic agents should be tailored for specific end-organ damage.
Topics: Humans; Antihypertensive Agents; Prospective Studies; Hypertension; Calcium Channel Blockers; Blood Pressure
PubMed: 37016936
DOI: 10.1097/HCO.0000000000001049 -
Hypertension Research : Official... Sep 2023Arterial hypertension is associated with increased morbidity and mortality and research in the field is highly dynamic. This summary reviews the most important clinical... (Review)
Review
Arterial hypertension is associated with increased morbidity and mortality and research in the field is highly dynamic. This summary reviews the most important clinical trials published in 2022 and early 2023. Findings on new pharmacological approaches to treat resistant hypertension are presented and new knowledge about the optimal timing of the antihypertensive medication intake is discussed. It is focused on optimal blood pressure treatment targets and the problem of treatment and guideline inertia is acknowledged. Information about pregnancy-related hypertension is presented and blood pressure control following percutaneous thrombectomy after ischemic stroke is discussed. Finally, novel clinical data on device-based approaches to treat hypertension are summarized. The hypertension trials update summarizes the most important clincal trials on hypertension research in 2022 and early 2023. CTD - chlorthalidone, CV - cardiovascular, HCT - hydrochlorothiazide, SBP - systolic blood pressure, RDN - renal denervation *depicts systolic blood pressure only.
Topics: Humans; Antihypertensive Agents; Blood Pressure; Chlorthalidone; Hypertension; Kidney; Sympathectomy; Treatment Outcome; Clinical Trials as Topic
PubMed: 37443261
DOI: 10.1038/s41440-023-01359-y -
JAMA Dec 2023Dietary sodium recommendations are debated partly due to variable blood pressure (BP) response to sodium intake. Furthermore, the BP effect of dietary sodium among... (Clinical Trial)
Clinical Trial
IMPORTANCE
Dietary sodium recommendations are debated partly due to variable blood pressure (BP) response to sodium intake. Furthermore, the BP effect of dietary sodium among individuals taking antihypertensive medications is understudied.
OBJECTIVES
To examine the distribution of within-individual BP response to dietary sodium, the difference in BP between individuals allocated to consume a high- or low-sodium diet first, and whether these varied according to baseline BP and antihypertensive medication use.
DESIGN, SETTING, AND PARTICIPANTS
Prospectively allocated diet order with crossover in community-based participants enrolled between April 2021 and February 2023 in 2 US cities. A total of 213 individuals aged 50 to 75 years, including those with normotension (25%), controlled hypertension (20%), uncontrolled hypertension (31%), and untreated hypertension (25%), attended a baseline visit while consuming their usual diet, then completed 1-week high- and low-sodium diets.
INTERVENTION
High-sodium (approximately 2200 mg sodium added daily to usual diet) and low-sodium (approximately 500 mg daily total) diets.
MAIN OUTCOMES AND MEASURES
Average 24-hour ambulatory systolic and diastolic BP, mean arterial pressure, and pulse pressure.
RESULTS
Among the 213 participants who completed both high- and low-sodium diet visits, the median age was 61 years, 65% were female and 64% were Black. While consuming usual, high-sodium, and low-sodium diets, participants' median systolic BP measures were 125, 126, and 119 mm Hg, respectively. The median within-individual change in mean arterial pressure between high- and low-sodium diets was 4 mm Hg (IQR, 0-8 mm Hg; P < .001), which did not significantly differ by hypertension status. Compared with the high-sodium diet, the low-sodium diet induced a decline in mean arterial pressure in 73.4% of individuals. The commonly used threshold of a 5 mm Hg or greater decline in mean arterial pressure between a high-sodium and a low-sodium diet classified 46% of individuals as "salt sensitive." At the end of the first dietary intervention week, the mean systolic BP difference between individuals allocated to a high-sodium vs a low-sodium diet was 8 mm Hg (95% CI, 4-11 mm Hg; P < .001), which was mostly similar across subgroups of age, sex, race, hypertension, baseline BP, diabetes, and body mass index. Adverse events were mild, reported by 9.9% and 8.0% of individuals while consuming the high- and low-sodium diets, respectively.
CONCLUSIONS AND RELEVANCE
Dietary sodium reduction significantly lowered BP in the majority of middle-aged to elderly adults. The decline in BP from a high- to low-sodium diet was independent of hypertension status and antihypertensive medication use, was generally consistent across subgroups, and did not result in excess adverse events.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04258332.
Topics: Aged; Female; Humans; Male; Middle Aged; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Diet, Sodium-Restricted; Hypertension; Sodium; Sodium Chloride, Dietary; Sodium, Dietary
PubMed: 37950918
DOI: 10.1001/jama.2023.23651 -
Nephrology, Dialysis, Transplantation :... Nov 2023Hypertension is very common and remains often poorly controlled in patients with chronic kidney disease (CKD). Accurate blood pressure (BP) measurement is the essential... (Review)
Review
Hypertension is very common and remains often poorly controlled in patients with chronic kidney disease (CKD). Accurate blood pressure (BP) measurement is the essential first step in the diagnosis and management of hypertension. Dietary sodium restriction is often overlooked, but can improve BP control, especially among patients treated with an agent to block the renin-angiotensin system. In the presence of very high albuminuria, international guidelines consistently and strongly recommend the use of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker as the antihypertensive agent of first choice. Long-acting dihydropyridine calcium channel blockers and diuretics are reasonable second- and third-line therapeutic options. For patients with treatment-resistant hypertension, guidelines recommend the addition of spironolactone to the baseline antihypertensive regimen. However, the associated risk of hyperkalemia restricts the broad utilization of spironolactone in patients with moderate-to-advanced CKD. Evidence from the CLICK (Chlorthalidone in Chronic Kidney Disease) trial indicates that the thiazide-like diuretic chlorthalidone is effective and serves as an alternative therapeutic opportunity for patients with stage 4 CKD and uncontrolled hypertension, including those with treatment-resistant hypertension. Chlorthalidone can also mitigate the risk of hyperkalemia to enable the concomitant use of spironolactone, but this combination requires careful monitoring of BP and kidney function for the prevention of adverse events. Emerging agents, such as the non-steroidal mineralocorticoid receptor antagonist ocedurenone, dual endothelin receptor antagonist aprocitentan and the aldosterone synthase inhibitor baxdrostat offer novel targets and strategies to control BP better. Larger and longer term clinical trials are needed to demonstrate the safety and efficacy of these novel therapies in the future. In this article, we review the current standards of treatment and discuss novel developments in pathophysiology, diagnosis, outcome prediction and management of hypertension in patients with CKD.
Topics: Humans; Spironolactone; Hyperkalemia; Chlorthalidone; Hypertension; Antihypertensive Agents; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Blood Pressure
PubMed: 37355779
DOI: 10.1093/ndt/gfad118 -
Nephrology, Dialysis, Transplantation :... Aug 2023Hypertension is the most common finding in chronic kidney disease patients, with prevalence ranging from 60% to 90% depending on the stage and etiology of the disease.... (Review)
Review
Hypertension is the most common finding in chronic kidney disease patients, with prevalence ranging from 60% to 90% depending on the stage and etiology of the disease. It is also a significant independent risk factor for cardiovascular disease, progression to end-stage kidney disease and mortality. According to the current guidelines, resistant hypertension is defined in the general population as uncontrolled blood pressure on three or more antihypertensive drugs in adequate doses or when patients are on four or more antihypertensive drug categories irrespective of the blood pressure control, providing that antihypertensive treatment included diuretics. The currently established definitions of resistant hypertension are not directly applicable to the end-stage kidney disease setting. The diagnosis of true resistant hypertension requires confirmation of adherence to therapy and confirmation of uncontrolled blood pressure values by ambulatory blood pressure measurement or home blood pressure measurement. In addition, the term "apparent treatment-resistant hypertension," defined as an uncontrolled blood pressure on three or more antihypertensive medication classes, or use of four or more medications regardless of blood pressure level was introduced. In this comprehensive review we focused on the definitions of hypertension, and therapeutic targets in patients on renal replacement therapy, including the limitations and biases. We discussed the issue of pathophysiology and assessment of blood pressure in the dialyzed population, management of resistant hypertension as well as available data on prevalence of apparent treatment-resistant hypertension in end-stage kidney disease. To conclude, larger sample-size and even higher quality studies about drug adherence should be conducted in the population of patients with the end-stage kidney disease who are on dialysis. It also should be determined how and when blood pressure should be measured in the group of dialysis patients. Additionally, it should be stated what the target blood pressure values in this group of patients really are. The definition of resistant hypertension in this group should be revisited, and its relationship to both subclinical and clinical endpoints should be established.
Topics: Humans; Antihypertensive Agents; Renal Dialysis; Blood Pressure Monitoring, Ambulatory; Hypertension; Blood Pressure; Kidney Failure, Chronic
PubMed: 36898677
DOI: 10.1093/ndt/gfad047 -
Primary Care Mar 2024Hypertension remains one of the most prevalent conditions encountered in the primary care setting and is a major contributor to cardiovascular disease in the United... (Review)
Review
Hypertension remains one of the most prevalent conditions encountered in the primary care setting and is a major contributor to cardiovascular disease in the United States. This reality underscores the importance for primary care clinicians to have an understanding of hypertension guidelines, interventions, and population-based considerations. This article provides a succinct overview of hypertension guidelines, reviews guideline-informed approaches to hypertension screening, diagnosis, and treatment, and concludes with a thoughtful discussion of population-based considerations.
Topics: Humans; United States; Antihypertensive Agents; Hypertension; Cardiovascular Diseases; Blood Pressure
PubMed: 38278572
DOI: 10.1016/j.pop.2023.07.002 -
Clinical Research in Cardiology :... Jul 2023Sacubitril/valsartan has been demonstrated to reduce blood pressure in hypertensive patients, but the best dose remains unclear. We performed this network meta-analysis... (Meta-Analysis)
Meta-Analysis Review
AIM
Sacubitril/valsartan has been demonstrated to reduce blood pressure in hypertensive patients, but the best dose remains unclear. We performed this network meta-analysis to determine the comparative efficacy and safety of three available doses of sacubitril/valsartan (i.e., 100, 200, and 400 mg).
METHODS AND RESULTS
We searched four databases for relevant studies published before January 2022. Mean systolic and diastolic blood pressures in the sitting position (msSBP and msDBP) and ambulatory condition (24-h maSBP and maDBP) and adverse events (AEs) were assessed. Nine randomized controlled trials (RCTs) involving 5474 patients were included. Sacubitril/valsartan 200 mg once daily was slightly better than 400 mg once daily in lowering 24-h maDBP (MD, 1.31 mmHg; 95% CI 0.61-2.01 mmHg), slightly better than 100 mg once daily in lowering 24-h maSBP (MD, - 3.70 mmHg; 95% CI - 6.22 to - 1.18 mmHg) and 24-h maDBP (MD, - 2.98; 95% CI - 5.11 to - 0.85), and slightly better than Valsartan 160 mg once daily in lowering 24-h maSBP (MD, - 3.23 mmHg; 95% CI, - 5.25 to - 1.21). 400 mg once daily of sacubitril/valsartan was better than 200 mg once daily in lowering msDBP (MD, - 9.38 mmHg; 95% CI - 17.79 to - 0.97 mmHg). Interestingly, 400 mg once daily of sacubitril/valsartan had fewer trial-specified AEs than 200 mg once daily (OR, 0.74; 95%CI 0.55-0.99). There was no statistical difference for the remaining comparisons.
CONCLUSIONS
In hypertensive patients, 200 mg once daily of sacubitril/valsartan may exert a greater reduction in ambulatory blood pressure than 100 mg once daily and 200 mg once daily may not be inferior to 400 mg once daily. Moreover, it is not clear that sacubitril/valsartan lowers blood pressure more than an angiotensin receptor blocker. Further trials are required to determine the incremental value of sacubitril/valsartan as an anti-hypertensive agent.
Topics: Humans; Network Meta-Analysis; Angiotensin II Type 1 Receptor Blockers; Tetrazoles; Valsartan; Hypertension; Essential Hypertension; Antihypertensive Agents; Blood Pressure; Drug Combinations; Angiotensin Receptor Antagonists; Randomized Controlled Trials as Topic
PubMed: 36326841
DOI: 10.1007/s00392-022-02120-0 -
Current Problems in Cardiology Nov 2023Hypertension is a global epidemic, affecting around 30.4% of the population and being the leading preventable risk factor for death. Despite the availability of numerous... (Review)
Review
Hypertension is a global epidemic, affecting around 30.4% of the population and being the leading preventable risk factor for death. Despite the availability of numerous antihypertensive agents, less than 20% of individuals have their blood pressure controlled. Resistant hypertension poses a challenge, but a new class of medication, aldosterone synthase inhibitors (ASI), shows promise. ASI reduces aldosterone production by inhibiting aldosterone synthase. This review article focuses on Baxdrostat, a highly potent ASI currently in phase 3 trials. It discusses the drug's biochemical pathway, efficacy trials in animals and humans, and its potential in uncontrolled hypertension, chronic kidney disease, and primary aldosteronism.
Topics: Animals; Humans; Aldosterone; Cytochrome P-450 CYP11B2; Hypertension; Antihypertensive Agents; Mineralocorticoid Receptor Antagonists
PubMed: 37399857
DOI: 10.1016/j.cpcardiol.2023.101918 -
Hypertension (Dallas, Tex. : 1979) Sep 2023Clinical practice guidelines are ideally suited to the provision of advice on the prevention, diagnosis, evaluation, and management of high blood pressure (BP). The...
Clinical practice guidelines are ideally suited to the provision of advice on the prevention, diagnosis, evaluation, and management of high blood pressure (BP). The recently published European Society of Hypertension (ESH) 2023 ESH Guidelines for the management of arterial hypertension is the latest in a long series of high BP clinical practice guidelines. It closely resembles the 2018 European Society of Cardiology/ESH guidelines, with incremental rather than major changes. Although the ESH guidelines are primarily written for European clinicians and public health workers, there is a high degree of concordance between its recommendations and those in the other major BP guidelines. Despite the large number of national and international BP guidelines around the world, general population surveys demonstrate that BP guidelines are not being well implemented in any part of the world. The level of BP, which is the basis for diagnosis and management, continues to be poorly measured in routine clinical practice and control of hypertension remains suboptimal, even to a conservative BP target such as a systolic/diastolic BP <140/90 mm Hg. BP guidelines need to focus much more on implementation of recommendations for accurate diagnosis and strategies for improved control in those being treated for hypertension. An evolving body of implementation science can assist in meeting this goal. Given the enormous health, social, and financial burden of high BP, better diagnosis and management should be an imperative for clinicians, government, and others responsible for the provision of health care services. Hopefully, the 2023 ESH will help enable this.
Topics: Humans; Antihypertensive Agents; Hypertension; Blood Pressure; Blood Pressure Determination; Cardiology
PubMed: 37354199
DOI: 10.1161/HYPERTENSIONAHA.123.21592