Cervical Ripening Efficacy of Synthetic Osmotic Cervical Dilator Compared With Oral Misoprostol at Term: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether a synthetic osmotic cervical dilator is noninferior to oral misoprostol for cervical ripening. METHODS: In an open-label, noninferiority randomized trial, pregnant women undergoing induction of labor at 37 weeks of gestation or more with Bishop scores less than 6 were randomized to either mechanical cervical dilation or oral misoprostol. Participants in the mechanical dilation group underwent insertion of synthetic osmotic cervical dilator rods, and those in the misoprostol group received up to six doses of 25 micrograms orally every 2 hours. After 12 hours of ripening, oxytocin was initiated, with artificial rupture of membranes. Management of labor was at the physician's discretion. The primary outcome was the proportion of women achieving vaginal delivery within 36 hours of initiation of study intervention. Secondary outcomes included increase in Bishop score, mode of delivery, induction-to-delivery interval, total length of hospital stay, and patient satisfaction. On the basis of a noninferiority margin of 10%, an expected primary outcome frequency of 65% for misoprostol and 71% for mechanical methods, and 85% power, a sample size of 306 participants was needed. RESULTS: From November 2018 through January 2021, 307 women were randomized, with 151 evaluable participants in the synthetic osmotic cervical dilator group and 152 in the misoprostol group (there were four early withdrawals). The proportion of women achieving vaginal delivery within 36 hours was higher with mechanical cervical dilation compared with misoprostol (61.6% vs 59.2%), with an absolute difference of 2.4% (95% CI -9% to 13%), indicating noninferiority for the prespecified margin. No differences were noted in the mode of delivery. Tachysystole was more frequent in the misoprostol group (70 [46.4%] vs 35 [23.3%]; P=.01). Participants in the synthetic osmotic cervical dilator group reported better sleep, less unpleasant abdominal sensations, and lower pain scores (P<.05). CONCLUSION: Synthetic osmotic cervical dilator is noninferior to oral misoprostol for cervical ripening. Advantages of synthetic osmotic cervical dilator include a better safety profile and patient satisfaction, less tachysystole, lower pain scores, and U.S. Food and Drug Administration approval. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03670836. FUNDING SOURCE: Medicem Technology s.r.o., Czech Republic.

Epidemiology of CYP3A4-mediated clopidogrel drug-drug interactions and their clinical consequences.

AIMS: Clopidogrel is a prodrug that needs to be activated to inhibit platelet aggregation. The objective of this study was to evaluate the prevalence and clinical consequences of potential drug-drug interactions of clopidogrel with drugs affecting CYP3A4 activity. METHODS: Co-administrations of clopidogrel together with well-established CYP3A4 inhibitors, CYP3A4 inducers, and atorvastatin were investigated in a population-based pharmacoepidemiological study utilizing data from the national healthcare registers and in more detail from a university hospital register in Finland. The main outcome measures were all-cause mortality and mortality and morbidity related to thrombosis or bleeding. RESULTS: In the nationwide analysis, 6.1%, 1.0%, and 20.8% of the clopidogrel-treated patients were exposed to concomitant use of CYP3A4 inhibitors, CYP3A4 inducers, and atorvastatin, respectively. In the survival analysis, the adjusted hazard ratio for overall mortality was 2.29 (P < 0.001) for CYP3A4 inducer users and 0.74 (P = 0.003) for atorvastatin users compared with controls (patients receiving clopidogrel without interacting medication). CYP3A4 inhibitor use seemed to prevent from thrombosis: HR 0.67, P < 0.001. The hospitalizations due to bleedings were rarer in atorvastatin and CYP3A4 inhibitor groups compared with controls. Thrombosis complications leading to hospitalizations were more often seen in the atorvastatin group than in the control group. CONCLUSIONS: No uniform untoward effect of concomitant CYP3A4 inhibitor use on the clinical efficacy of clopidogrel was found. In patients receiving concomitant atorvastatin and clopidogrel, the antithrombotic effect of clopidogrel was moderately attenuated, but the combination significantly reduced the overall mortality. CYP3A4 inhibitors and atorvastatin may reduce bleedings in clopidogrel users.

Association between low plasma levels of ophthalmic timolol and haemodynamics in glaucoma patients.

OBJECTIVES: The aims of the study were to assess the correlation between the plasma concentration of ophthalmic timolol and cardiovascular parameters, and the influence of timolol on advanced haemodynamic variables, such as stroke (SI), cardiac (CI) and systemic vascular resistance (SVRI) indices and arterial pulse wave velocity (PWV). METHODS: Twenty-five glaucoma or ocular hypertensive patients were treated with 0.5% aqueous and 0.1% hydrogel formulations of timolol using a randomised, double-masked, crossover, multicentre design. All the patients were subjected to passive head-up tilt, electrocardiography, exercise test and measurement of plasma concentration of timolol. In the analysis, the data on the two treatments were combined, and the Spearman correlation coefficients between the plasma level of timolol and physiological effects were calculated. RESULTS: During the head-up tilt test before rising the bed up, the resting heart rate (HR; R=-0.52, P=0.001) and PWV (R=-0.34, P=0.04) were inversely correlated with timolol level. In the upright position, ophthalmic timolol effectively suppressed the rise in HR (R=-0.36, P=0.03). The SI did not change with timolol concentration, while CI diminished as timolol concentration rose (R=-0.39, P=0.02). The SVRI correlated with timolol concentration (R=0.38, P=0.02). In the exercise test, correlation between HR and plasma level of timolol steadily grew stronger as the load increased, reaching R=-0.60 (P<0.0001) at the maximum load. Systolic and diastolic arterial pressures were not associated with the timolol concentration. CONCLUSION: The plasma concentration of ophthalmic timolol correlates with several haemodynamic effects. As HR decreases, SVRI increases and blood pressure is kept unchanged.