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- Gheorghiade, Mihai, et al.
(författare)
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Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction : The SOCRATES-REDUCED Randomized Trial.
- 2015
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 314:21, s. 2251-2262
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: Worsening chronic heart failure (HF) is a major public health problem.OBJECTIVE: To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF).DESIGN, SETTING, AND PARTICIPANTS: Dose-finding phase 2 study that randomized 456 patients across Europe, North America, and Asia between November 2013 and January 2015, with follow-up ending June 2015. Patients were clinically stable with LVEF less than 45% within 4 weeks of a worsening chronic HF event, defined as worsening signs and symptoms of congestion and elevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic.INTERVENTIONS: Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg [n = 91], 2.5 mg [n = 91], 5 mg [n = 91], 10 mg [n = 91]) for 12 weeks.MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline to week 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis evaluated a dose-response relationship with vericiguat and the primary end point.RESULTS: Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969; 12 weeks, 7.567; difference, -0.402; geometric means: baseline, 2890 pg/mL; 12 weeks, 1932 pg/mL) and placebo (log-transformed: baseline, 8.283; 12 weeks, 8.002; difference, -0.280; geometric means: baseline, 3955 pg/mL; 12 weeks, 2988 pg/mL) (difference of means, -0.122; 90% CI, -0.32 to 0.07; ratio of geometric means, 0.885, 90% CI, 0.73-1.08; P = .15). The exploratory secondary analysis suggested a dose-response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level (P < .02). Rates of any adverse event were 77.2% and 71.4% among the placebo and 10-mg vericiguat groups, respectively.CONCLUSIONS AND RELEVANCE: Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well-tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF.TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01951625.
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- Goisis, Alice, et al.
(författare)
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Birth outcomes following assisted reproductive technology conception among same-sex lesbian couples vs natural conception and assisted reproductive technology conception among heterosexual couples
- 2023
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Ingår i: Journal of the American Medical Association (JAMA). - 0098-7484 .- 1538-3598. ; 329:13, s. 1117-1119
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Tidskriftsartikel (refereegranskat)abstract
- Higher rates of adverse birth outcomes have been consistently reported among children conceived via assisted reproductive technology (ART) compared with children conceived through natural conception. Higher rates of multiple births in ART pregnancies partially explain the increased risk. It remains unclear to what extent the remaining difference can be attributed to the reproductive technology or to factors related to infertility, which is associated with an elevated risk of poorer birth outcomes. Same-sex lesbian couples undergo ART treatments generally without experiencing infertility. To distinguish the effects of reproductive treatment and infertility, we compared birth outcomes in ART pregnancies among same-sex lesbian couples vs natural conceptions and ART pregnancies among heterosexual couples.Methods: In Sweden, same-sex lesbian couples have been eligible to receive publicly funded ART treatments with donated sperm since 2005. This study included all births in Sweden from 2007 to 2018. Using pseudonymized personal identifiers, the Swedish National Quality Registry for Assisted Reproduction, which includes all ART treatments (in vitro fertilization [IVF], intracytoplasmic sperm injection [ICSI], and intrauterine insemination [IUI]), was linked to the medical birth register and the total population registers, which include information on birth outcomes and sociodemographic characteristics. We focused on first live births for ART and naturally conceived births because 97.3% of ART births among same-sex lesbian couples were first births. We analyzed 4 outcomes: birth weight (continuous), gestational age (continuous), low birth weight (binary, <2500 g), and preterm delivery (binary, <37 weeks of gestation). We estimated linear models on the continuous outcomes and linear probability models on the binary outcomes comparing ART-conceived births among same-sex lesbian couples (reference category) with ART births and naturally conceived births among heterosexual couples. For each outcome, we estimated unadjusted and adjusted (controlling for child sex, multiplicity, and maternal age at birth) models. We also estimated differences focusing on children conceived via IVF/ICSI because 99.4% of ART births among heterosexual couples were conceived via IVF/ICSI compared with 63.3% in same-sex couples, as same-sex couples often start treatments with IUI, which has a lower chance of success regardless of subfertility.Analyses were conducted using R version 4.1.1 (R Foundation). Statistical significance was set at P < .05 (2-sided). This study was approved by the Regional Ethical Review Board of Stockholm. Informed consent was not required for pseudonymized data.Results: During the study period, there were 868 ART births among same-sex lesbian couples, 23 488 ART births among heterosexual couples, and 456 898 naturally conceived births. ART-conceived births from same-sex and heterosexual couples showed a higher proportion of multiplicity (5.8% and 7.5%, respectively) than naturally conceived births (2.1%) (Table 1). Couples who conceived naturally had significantly lower birth weight and gestational age and similar risk of low birth weight and preterm delivery compared with same-sex couples who conceived via ART (Table 2). For example, birth weight was 3429.5 g in naturally conceived births vs 3460.2 g in same-sex ART births (adjusted difference, −76.2 g [95% CI, −113 to −39.3 g]; P < .001; low birth weight, 4.9% vs 6.7%, adjusted difference, 0.28 [95% CI, −1.11 to 1.66] percentage points; P = .70). Heterosexual couples who conceived via ART had statistically significantly lower birth weight and gestational age than same-sex couples (eg, birth weight: 3342.9 g vs 3460.2 g; adjusted difference, −97.4 g [95% CI, −134.8 to −59.9 g]; P < .001). Percentages of low birth weight and preterm birth were higher in ART conceptions among heterosexual couples vs same-sex couples but did not reach statistical significance (eg, low birth weight: 8.9% vs 6.7%; adjusted difference, 1.23 [95% CI, −0.17 to 2.65] percentage points; P = .09). The results were qualitatively similar when only considering IVF/ICSI-conceived children (Table 2).Discussion: This study demonstrated that same-sex lesbian couples undergoing ART had more favorable or similar birth outcomes to heterosexual couples who conceived naturally or underwent ART to conceive, suggesting that infertility-related factors rather than reproductive treatments contribute to higher rates of adverse birth outcomes in ART pregnancies. Limitations of the study include that the presence of infertility factors was not directly assessed and the relatively small sample size of same-sex couples reduced the statistical power of the study, particularly in the binary outcomes analyses.
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