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- Johnson, Miriam J., et al.
(författare)
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No excess harms from sustained-release morphine : A randomised placebo-controlled trial in chronic breathlessness
- 2020
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Ingår i: BMJ Supportive and Palliative Care. - : BMJ. - 2045-435X .- 2045-4368. ; 10:4, s. 421-428
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: We aimed to identify and evaluate: (1) treatment-emergent adverse events (TEAE (worse or new since baseline)) and the subgroup of severe TEAEs in a placebo-controlled 7-day randomised trial of regular, low-dose, sustained-release oral morphine for chronic breathlessness and (2) clinical characteristics associated with TEAE. Methods: Safety analysis of trial data. Adults with chronic breathlessness (modified Medical Research Council breathlessness score ≥2) due to heart or lung disease, or cancer, not on regular opioids were eligible. Symptoms associated with opioids (TEAE of special interest) were systematically sought using Common Terminology Criteria for Adverse Events (CTCAE) grading. Other harms could be reported at any time. The relationship between characteristics and presence of ≥1 TEAE of special interest was explored using univariable logistic regression analyses. Results: 1449/5624 (26%) Adverse Events from 279 participants were TEAE of which 150/1449 (10%) were severe (CTCAE grades 3-5). 1086/5624 (75%) were events of special interest of which 41/1086 (4%) were severe. Compared with placebo, morphine was not associated with more TEAE or severe TEAE of special interest (TEAE: OR 0.53, 95% CI 0.21 to 1.38, p=0.20; severe TEAE: OR 0.96, 95% CI 0.27 to 3.41, p=0.95) nor with CTCAE severity grade (χ2=4.39, p=0.50). Among the 26/150 (17%) with severe TEAEs, study withdrawal was more common in the morphine arm (18/26 (69%) morphine arm; 8/26 (30%) placebo arm). None of the severe TEAEs was a respiratory harm. Conclusions: Severe morphine-associated toxicity was uncommon and not associated with study arm. Clinical consequences were minor and self-limiting.
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| 2. |
- Schmidt, Amand F., et al.
(författare)
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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- 2019
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Ingår i: BMC Cardiovascular Disorders. - : BMC. - 1471-2261 .- 1471-2261. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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