Emerging treatments

Your Organizational Guidance

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Cardiovasculaire risicobepaling in de eerste lijnPublished by: Domus MedicaLast published: 2020Évaluation du risque cardiovasculaire en première lignePublished by: Domus MedicaLast published: 2010

Chronotherapy

Studies have investigated whether hypertension therapy taken at bedtime results in improved cardiovascular disease (CVD) risk reduction compared with medication taken upon awakening. The Hygia Chronotherapy Trial, conducted in primary care, found that hypertensive patients taking ≥1 prescribed blood pressure (BP)-lowering medications at bedtime had improved ambulatory BP control compared with those who took their medications upon awakening, and they also had a reduced occurrence of major CVD events.[177] However, excessive lowering of nocturnal BP with nighttime dosing may increase the potential risk of retinal, cerebral, and myocardial ischemia, and may lower medication adherence. The Treatment in Morning versus Evening (TIME) study compared evening and morning dosing of usual antihypertensive medication in participants followed up for a median of 5.2 years and found no difference between the groups for the primary composite outcome of vascular death or hospitalization for nonfatal myocardial infarction.[178]​ One Cochrane review found very limited data to determine whether evening or morning dosing has more beneficial effects on cardiovascular outcomes or adverse events.[179]​ The 2023 European guidelines note that patients have a choice as to when to take hypertension therapy, but that adherence is generally better in the morning.[63] The 2024 ESC guidelines conclude that there is no reliable evidence to support bedtime dosing as a superior strategy and emphasize that patient choice and drug adherence should guide the timing of hypertension therapy.[1] Preliminary findings from the BedMed and BedMed Frail trials, presented at the 2024 ESC meeting, reported no significant benefit of bedtime dosing for cardiovascular outcomes. These findings have not yet been published in peer-reviewed journals.[1]​​​ Bedtime dosing may be considered in patients with documented high nighttime BP.

Renal sympathetic denervation

Activation of renal sympathetic nerves is a component of essential hypertension pathophysiology. Over the years, renal denervation studies have reported variable efficacy results; however, several randomized, sham-controlled trials have now shown BP lowering for both radiofrequency and ultrasound renal denervation in patients with mild-to-moderate, severe, and resistant hypertension.[180][181][182][183][184][185][186][187][188][189][190]​​​​​​[191][192][193][194]​​​​​​​​​​​​​​​[195][196][197] [ Cochrane Clinical Answers logo ] ​​​​ In November 2023, the US Food and Drug Administration approved renal denervation as an adjunctive treatment for patients whose BP is inadequately controlled with lifestyle modifications and antihypertensive drugs.[198]​ The European guidelines now suggest that renal denervation may be considered as an adjunctive or alternative treatment option in patients with uncontrolled and resistant hypertension despite lifestyle and pharmacologic interventions, and may also be an option for those unable to tolerate long-term antihypertensive medication.[63][199]

Baroreflex activation therapy

Electrical stimulation of the carotid sinus baroreflex system, also known as baroreflex activation therapy (BAT), may decrease BP in patients with resistant hypertension. Electric stimulators directly activating afferent baroreflex nerves have previously failed in trials for technical reasons. However, a novel implantable device may overcome some of the previously experienced technical problems. The device stimulates the carotid sinus wall and has been shown to reduce BP in feasibility studies.[200][201][202] In the Rheos Pivotal trial, which assessed long-term BP control in resistant-hypertension patients receiving BAT, BP reduction was maintained over long-term follow-up of 22-53 months.[203]

L-arginine supplementation

Oral supplementation with L-arginine, an amino acid and a substrate of nitric oxide synthase, has been shown to significantly lower both systolic and diastolic BP.[204]

Vitamin C supplementation

Vitamin C supplementation has been shown to reduce systolic and diastolic BP in short-term trials. Long-term trials examining the effects of vitamin C supplementation on BP and clinical events are needed.[205][206]

Vitamin D supplementation

Data from cross-sectional studies report that low levels of 25-hydroxy vitamin D are associated with higher systolic BP and higher incidence of hypertension.[207] Large observational studies show a weaker, yet similar, association. This effect is thought to be partly mediated through regulation of the renin-angiotensin-aldosterone axis.[208] Randomized controlled trials conflict with observational data, probably due to differences in populations studied, doses of vitamin D used, and unmeasured confounders. One systematic review found that in studies to date, vitamin D supplementation was ineffective for BP lowering.[209] Large randomized trials focusing on patients with severe vitamin D deficiency and hypertension are needed before vitamin D can be recommended for the prevention or treatment of hypertension.

Calcium supplementation

Data indicate that increased calcium intake slightly reduces systolic and diastolic BP in people with normal BP, particularly young people. This could have implications for prevention and public health, but more and larger studies are needed.[210]

Amiloride

In the PATHWAY-2 study of resistant hypertension, the potassium-sparing diuretic amiloride was shown to be as effective at reducing BP as spironolactone, suggesting it may be an alternative option for resistant hypertension.[211]

Baxdrostat

In one phase 2 trial, baxdrostat, an aldosterone synthase inhibitor, was shown to reduce BP in patients with resistant hypertension over 12 weeks compared with placebo. Reductions were dose-related.[212]

Lorundrostat

Lorundrostat is an aldosterone synthase inhibitor being investigated as a treatment for high BP. In one randomized controlled trial of adults with uncontrolled hypertension taking two or more antihypertensive drugs, use of lorundrostat decreased BP significantly more than placebo and was well tolerated.[213]​ Further confirmatory studies are now needed.

Aprocitentan

Aprocitentan is a novel dual endothelin receptor antagonist that has been approved in the US for the treatment of hypertension in combination with other antihypertensive drugs, to lower BP in adult patients who are not adequately controlled on other drugs. In one phase 3, multicenter trial (PRECISION), aprocitentan reduced BP compared with placebo at 4 weeks of treatment.[214]

Zilebesiran

Zilebesiran is an investigational RNA interference therapeutic agent that inhibits synthesis of hepatic angiotensinogen (the precursor of all angiotensin peptides). One phase 1 study, found that patients receiving zilebesiran had decreases in serum angiotensinogen and BP that were sustained for up to 24 weeks.[215]​ One phase 2 study found that in adults with mild to moderate hypertension, zilebesiran given across a range of doses at 3- or 6-month intervals significantly decreased 24-hour mean ambulatory systolic BP at 6 months compared with placebo.[216]

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