In patients with chronic kidney disease, SGLT2 inhibitors and endothelin A receptor antagonists (ERAs) can reduce albuminuria and glomerular filtration rate (GFR) decline. We assessed the ...albuminuria-lowering efficacy and safety of the ERA zibotentan combined with the SGLT2 inhibitor dapagliflozin.
ZENITH-CKD was a multicentre, randomised, double-blind, active-controlled clinical trial, done in 170 clinical practice sites in 18 countries. Adults (≥18 to ≤90 years) with an estimated GFR (eGFR) of 20 mL/min per 1·73 m
or greater and a urinary albumin-to-creatinine ratio (UACR) of 150-5000 mg/g were randomly assigned (2:1:2) to 12 weeks of daily treatment with zibotentan 1·5 mg plus dapagliflozin 10 mg, zibotentan 0·25 mg plus dapagliflozin 10 mg, or dapagliflozin 10 mg plus placebo, as adjunct to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers if tolerated. The primary endpoint was a change from baseline in log-transformed UACR (zibotentan 1·5 mg plus dapagliflozin vs dapagliflozin plus placebo) at week 12. Fluid retention was an event of special interest, defined as an increase in bodyweight of at least 3% (at least 2·5% must have been from total body water) from baseline or an increase of at least 100% in B-type natriuretic peptide (BNP) and either a BNP concentration greater than 200 pg/mL if without atrial fibrillation or BNP greater than 400 pg/mL if with atrial fibrillation. This trial is registered with ClinicalTrials.gov, NCT04724837, and is completed.
Between April 28, 2021, and Jan 17, 2023, we assessed 1492 participants for eligibility. For the main analysis, we randomly assigned 449 (30%) participants, 447 (99%) of whom (mean age 62·8 years SD 12·1, 138 31% female, 309 69% male, 305 68% White, mean eGFR 46·7 mL/min per 1·73 m
SD 22·4, and median UACR 565·5 mg/g IQR 243·0-1212·6) received treatment with zibotentan 1·5 mg plus dapagliflozin (n=179 40%), zibotentan 0·25 mg plus dapagliflozin (n=91 20%), or dapagliflozin plus placebo (n=177 40%). Zibotentan 1·5 mg plus dapagliflozin and zibotentan 0·25 mg plus dapagliflozin reduced UACR versus dapagliflozin plus placebo throughout the treatment period of the study. At week 12, the difference in UACR versus dapagliflozin plus placebo was -33·7% (90% CI -42·5 to -23·5; p<0·0001) for zibotentan 1·5 mg plus dapagliflozin and -27·0% (90% CI -38·4 to -13·6; p=0·0022) for zibotentan 0·25 mg plus dapagliflozin. Fluid-retention events were observed in 33 (18%) of 179 participants in the zibotentan 1·5 mg plus dapagliflozin group, eight (9%) of 91 in the zibotentan 0·25 mg plus dapagliflozin group, and 14 (8%) of 177 in the dapagliflozin plus placebo group.
Zibotentan combined with dapagliflozin reduced albuminuria with an acceptable tolerability and safety profile and is an option to reduce chronic kidney disease progression in patients already receiving currently recommended therapy.
AstraZeneca.
Pulmonary arterial hypertension (PAH) affects people of all ages and is associated with poor prognosis. Chronic breathlessness affects almost all people with PAH.
This randomized, placebo-controlled, ...double-blind, crossover study aimed to evaluate the effects of regular, low-dose, extended-release (ER) morphine for PAH-associated chronic breathlessness.
Participants with PAH-associated chronic breathlessness were randomized to 1) seven days of ER morphine 20 mg, 2) seven-day washout, and 3) seven days of identically looking placebo, or vice versa. Primary end points were breathlessness “right now”—morning and evening—measured with a Visual Analogue Scale. Secondary end points included additional breathlessness measures, quality of life, function, harms, and blinded treatment preference (ACTRN12609000209291).
Within a period of seven years, 50 patients were assessed in detail and 23 (46%) were randomized (despite broad eligibility criteria). Four participants withdrew while taking morphine. Nineteen participants completed the study. Breathlessness “right now” was higher on morphine compared with placebo both for morning mean (M) ± SD 31.7 ± 25 mm vs. 26.9 ± 22 mm; effect size (80% CI) = −0.22 (−0.6 to 0.2) and evening (M ± SD 33.5 ± 28 mm vs. 25.6 ± 21 mm; effect size (80% CI) = −0.33 (−0.8 to 0.1). All secondary measures of breathlessness were higher with morphine as were nausea and constipation.
This study does not support a Phase III study of ER morphine for people with PAH-associated chronic breathlessness. Recruiting to the target sample size was difficult, the direction of effect in every measure of breathlessness favored placebo and morphine generated more harms.
Background and objective
Recall of breathlessness is important for clinical care but might differ from the experienced (momentary) symptoms. This study aimed to characterize the relationship between ...momentary breathlessness ratings and the recall of the experience. It is hypothesized that recall is influenced by the peak (worst) and end (most recent) ratings of momentary breathlessness (peak‐end rule).
Methods
This study used mobile ecological momentary assessment (mEMA) for assessing breathlessness in daily life through an application installed on participants' mobile phones. Breathlessness ratings (0–10 numerical rating scale) were recorded throughout the day and recalled each night and at the end of the week. Analyses were performed using regular and mixed linear regression.
Results
Eighty‐four people participated. Their mean age was 64.4 years, 60% were female and 98% had modified Medical Research Council (mMRC) ≥ 1. The mean number of momentary ratings of breathlessness provided was 7.7 ratings/participant/day. Recalled breathlessness was associated with the mean, peak and end values of the day. The mean was most closely associated with the daily recall. Associations were strong for weekly values: peak breathlessness (beta = 0.95, r2 = 0.57); mean (beta = 0.91, r2 = 0.53); and end (beta = 0.67, r2 = 0.48); p < 0.001 for all. Multivariate analysis showed that peak breathlessness had the strongest influence on the breathlessness recalled at the end of the week.
Conclusion
Over 1 week, recalled breathlessness is most strongly influenced by the peak breathlessness; over 1 day, it is mean breathlessness that participants most readily recalled.
Recall of breathlessness is essential for clinical care but might differ from the momentary symptoms. This study reports that the peak momentary breathlessness most strongly influences recalled breathlessness over the past 7 days. Recall for 1 day was influenced the most by the mean breathlessness value for that day.
See related Editorial
Ninhydrin bis-acetals give access to 8-ring lactones, benzocyclo-butenes and spirocyclic orthoanhydrides through photoextrusion and tandem photoextrusion reactions. Syntheses of fimbricalyxlactone B, ...isoshihunine and numerous biologically-relevant heterocycles show the value of the methods, while TA-spectroscopy and TD-DFT studies provide mechanistic insights on their wavelength dependence.
Ninhydrin bis-acetals give access to 8-ring lactones, benzocyclobutenes and spirocyclic orthoanhydrides through photoextrusion and tandem photoextrusion reactions.
Chronic breathlessness: re-thinking the symptom Johnson, Miriam J; Yorke, Janelle; Hansen-Flaschen, John ...
The European respiratory journal,
04/2018, Letnik:
51, Številka:
4
Journal Article
Recenzirano
Odprti dostop
We agree with much presented by Mcnaughton et al. 1 in their response to our proposed chronic breathlessness syndrome, and appreciate their supportive comments 2. In particular, we agree that ...patients and their carers must be at the centre of the next steps, as we stated, “Importantly, the involvement of patients and family caregivers in the development of consensus can now be addressed given the frame which this initial work provides” 2.
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