Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial

BACKGROUND: Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension. METHODS: PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174. FINDINGS: The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square mean (SE) change in office systolic blood pressure at 4 weeks was -15·3 (SE 0·9) mm Hg for aprocitentan 12·5 mg, -15·2 (0·9) mm Hg for aprocitentan 25 mg, and -11·5 (0·9) mm Hg for placebo, for a difference versus placebo of -3·8 (1·3) mm Hg (97·5% CI -6·8 to -0·8, p=0·0042) and -3·7 (1·3) mm Hg (-6·7 to -0·8; p=0·0046), respectively. The respective difference for 24 h ambulatory systolic blood pressure was -4·2 mm Hg (95% CI -6·2 to -2·1) and -5·9 mm Hg (-7·9 to -3·8). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5·8 mm Hg, 95% CI 3·7 to 7·9, p<0·0001). The most frequent adverse event was mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12·5 mg, 25 mg, and placebo, during the 4-week double-blind part, respectively. This event led to discontinuation in seven patients treated with aprocitentan. During the trial, a total of 11 treatment-emergent deaths occurred, none of which were regarded by the investigators to be related to study treatment. INTERPRETATION: In patients with resistant hypertension, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4 with a sustained effect at week 40. FUNDING: Idorsia Pharmaceuticals and Janssen Biotech

Factors Affecting Fruit Quality in Strawberries Grown in a Subtropical Environment

Variations of strawberry fruit quality due to year, harvest date, cultivar, and nutrition were studied in Tucumán, Argentina. ‘Camarosa’, ‘Camino Real’, ‘Candonga’, and ‘Ventana’ were fertilized with “C” (control; 120 kg N/ha, 70 kg P2O5/ha, 220 kg K2O/ha, 40 kg CaO/ha, and 20 kg MgO/ha) and “1.5C” in 2006, “C”, “1.33C”, and “1.66C” in 2007, and “C”, “1.5C”, and “2C” in 2008, without affecting fruit quality. Fruit weight decreased with temperature and crop load. Firmness decreased with rainfall and temperature. Redness increased with temperature and decreased with rainfall. Soluble solids content decreased with crop load. Titratable acidity increased with temperature.EEA FamailláFil: Agüero, Juan José. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Famaillá. División Frutihorticultura; ArgentinaFil: Salazar, Sergio Miguel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Famaillá. División Frutihorticultura; ArgentinaFil: Kirschbaum, Daniel Santiago. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Famaillá. División Frutihorticultura; ArgentinaFil: Jerez, Elena Fanny. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Famaillá. División Frutihorticultura; Argentin

Homogeneous zones of vegetation index for characterizing variability and site-specific management in vineyards

Characterization of the spatial variability of vegetative vigor in vineyards can help improve the performance of site-specific management practices, or the management of vineyards with different rates. Characterization using canopy proximal sensing has been a widely disseminated technique; however, vineyards in southeastern Brazil, where the utilization of annual double pruning results in a winter harvest, knowledge of the role of variability in improving vineyard management has not yet been applied. This study aimed to determine if post-veraison mapping of a normalized difference vegetation index could be used to assess the variability in grapevine vigor, water status, physiology, yield and berry quality attributes at harvest in an irrigated vineyard in southeastern Brazil. This normalized difference vegetation index was measured with an active canopy sensor, and spatial distribution maps over two growing seasons of a vineyard, managed on an annual double pruning basis, were generated. Attributes of physiological and technological berry maturation, leaf water potential, gas exchange, production, and fresh pruning weight were calculated. These normalized difference vegetation index maps allowed for the determination of variability in vegetative vigor and the productive potential of the vineyard; however, high levels of rainfall during the maturation period may reduce the potential of using these maps for determining berry parameters