Psychotropic medication in pregnancy and lactation and early development of exposed children.

There is still limited knowledge about alterations of blood concentrations of psychotropic drugs during pregnancy, the transfer of psychotropic drugs into breastmilk and the effects on exposed children. We investigated changes in concentrations of psychopharmacological medication during pregnancy and lactation in serum and breastmilk at different time points in a naturalistic sample of 60 mothers and observed the development of the exposed children in the first 12 months. We found a decrease in serum concentrations from the first to the second trimester of amitriptyline, duloxetine, escitalopram, quetiapine and sertraline. Citalopram stayed rather stable during pregnancy, sertraline levels interestingly increased again from the second to the third trimester. High concentration-by-dose ratios in breastmilk were found for venlafaxine as well as lamotrigine, low for quetiapine and clomipramine. Similarly, clomipramine and quetiapine showed low milk/serum-penetration ratios. Regarding the birth outcome measures in children, we found no significant differences between in utero exposed compared to nonexposed newborns. There were no significant differences in the development in the first 12 months. Psychotropic medication in the peripartum needs a balancing of risks and benefits and a continuous therapeutic drug monitoring can be a guidance for clinicians to monitor drug alteration patterns, which are likely to occur due to physiological pregnancy-associated changes in pharmacokinetics. Accordingly, therapeutic drug monitoring can optimize a medication in pregnancy and lactation with the lowest effective dose.

Lithium Medication in Pregnancy and Breastfeeding-A Case Series.

Lithium salts are the first-line prophylaxis treatment for bipolar disorder in most guidelines. The majority of bipolar women are treated with mood stabilizers at the time they wish to get pregnant. One reason for this is the rising average age at first childbirth, at least in the high-income countries, which increases in general the likelihood of a medication with psychotropic drugs. Previously, lithium exposition during pregnancy was thought to strongly increase the risk of severe cardiac malformation. However, recent studies only point to a low teratogenic risk, so nowadays an increasing number of women are getting pregnant with ongoing lithium treatment. Regarding lithium medication during breastfeeding, there is evidence that lithium transfers to the breastmilk and can also be detected in the infants' serum. The influence on the infant is still a largely understudied topic. Regular monitoring of the infants' renal clearance, thyroid function, and lithium levels is warranted when breastfeeding under lithium exposure. In this case series, we present three case reports of bipolar mothers who were treated with lithium during pregnancy and breastfeeding to add to the scarce literature on this important topic. In short, we strengthen the importance of therapeutic drug monitoring due to fluctuating plasma levels during pregnancy and after birth, and we can report the birth and development of three healthy infants despite lithium medication during pregnancy and breastfeeding.

Enhanced platelet inhibition by clopidogrel and risk of bleeding in patients requiring oral anticoagulation after drug-eluting stent implantation.

AIMS: Clopidogrel is the P2Y12 inhibitor of choice in patients who undergo PCI and have an indication for oral anticoagulation (OAC). Prediction of the bleeding risk is of major interest in this population. The aim of this analysis was to investigate whether an enhanced platelet inhibition by clopidogrel measured by platelet function testing (PFT) with the Multiplate Analyzer is associated with an increased bleeding risk in patients on triple antithrombotic therapy. METHODS AND RESULTS: This investigation was performed in a cohort of 524 patients from the randomised ISAR-TRIPLE trial; 458 (87.4%) had PFT results available in the first 24 hours after PCI. Patients belonging to the lowest quintile according to PFT were considered as enhanced responders to clopidogrel. The primary endpoint was major bleeding according to TIMI criteria at nine months. The median of ADP-induced platelet aggregation in the whole population was 163 AU*min (107-241). Patients in the lowest quintile had values below 93 AU*min. These enhanced responders (92 patients) had a significantly higher risk of TIMI major bleeding (hazard ratio [HR] 3.13, 95% confidence interval [CI]: 1.38-7.09, p=0.01) and overall mortality (HR 3.42, 95% CI: 1.55-7.52, p=0.004) compared with the remaining patients (366 patients). No significant difference was observed for the secondary combined ischaemic endpoint (HR 1.27, 95% CI: 0.47-3.47, p=0.64). CONCLUSIONS: Enhanced platelet inhibition delivered by clopidogrel is associated with an increased risk for major bleeding and death in patients on OAC who undergo PCI. These results support the use of PFT to identify patients with an increased risk for bleeding.

Duration of Triple Therapy in Patients Requiring Oral Anticoagulation After Drug-Eluting Stent Implantation: The ISAR-TRIPLE Trial.

BACKGROUND: Patients receiving oral anticoagulation (OAC) who undergo drug-eluting stent (DES) implantation require additional dual antiplatelet therapy with aspirin and clopidogrel. Such triple therapy confers an elevated bleeding risk, and its optimal duration is not known. OBJECTIVES: The goal of this study was to evaluate whether shortening the duration of clopidogrel therapy from 6 months to 6 weeks after DES implantation was associated with a superior net clinical outcome in patients receiving concomitant aspirin and OAC. METHODS: In this randomized, open-label trial, we enrolled patients receiving OAC who underwent DES implantation at 3 European centers between September 2008 and December 2013. A total of 614 patients receiving concomitant aspirin and OAC were randomized to either 6-week clopidogrel therapy (n=307) or 6-month clopidogrel therapy (n=307). The primary endpoint was a composite of death, myocardial infarction (MI), definite stent thrombosis, stroke, or Thrombolysis In Myocardial Infarction (TIMI) major bleeding at 9 months. RESULTS: The primary endpoint occurred in 30 patients (9.8%) in the 6-week group compared with 27 patients (8.8%) in the 6-month group (hazard ratio [HR]: 1.14; 95% CI: 0.68 to 1.91; p=0.63). There were no significant differences for the secondary combined ischemic endpoint of cardiac death, MI, definite stent thrombosis, and ischemic stroke (12 [4.0%] vs. 13 [4.3%]; HR: 0.93; 95% CI: 0.43 to 2.05; p=0.87) or the secondary bleeding endpoint of TIMI major bleeding (16 [5.3%] vs. 12 [4.0%]; HR: 1.35; 95% CI: 0.64 to 2.84; p=0.44). CONCLUSIONS: Six weeks of triple therapy was not superior to 6 months with respect to net clinical outcomes. These results suggest that physicians should weigh the trade-off between ischemic and bleeding risk when choosing the shorter or longer duration of triple therapy. (Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation [ISAR-TRIPLE]; NCT00776633).

Procedure-related bleeding in elective percutaneous coronary interventions.

BACKGROUND: Prognostic impact of procedure-related bleeding in patients with stable coronary artery disease (CAD) undergoing elective percutaneous coronary intervention (PCI) remains incompletely investigated. The aim of this study was to investigate the association between peri-PCI bleeding and 1-year outcome of patients with stable CAD. MATERIALS AND METHODS: The study included 9035 patients with stable CAD who underwent elective PCI. Bleeding within 30 days of PCI was defined using the Bleeding Academic Research Consortium (BARC) criteria. The primary outcome was 1-year mortality. RESULTS: Bleeding occurred in 844 patients (9.3%). Actionable bleeding (BARC class ≥ 2) occurred in 442 patients (4.9%). There were 210 deaths (2.3%) at 1 year following PCI: 41 deaths among patients with bleeding and 169 deaths among patients without bleeding [Kaplan-Meier estimates of mortality, 4.9% and 2.1%; odds ratio = 2.41, 95% confidence interval (CI) 1.73-3.36, P < 0.001]. The association between bleeding and mortality remained significant after adjustment for baseline risk variables (adjusted hazard ratio = 1.87, 95% CI 1.27-2.76, P = 0.002). Bleeding increased the discriminatory power of the model regarding prediction of 1-year mortality (absolute and relative integrated discrimination improvement, 0.006% and 16.3%, respectively, P = 0.001). CONCLUSIONS: In patients with stable CAD undergoing elective PCI, the occurrence of bleeding within 30 days of the procedure was associated with increased risk of death at 1 year after PCI. These findings suggest that procedure-related bleeding may contribute to less than optimal results of PCI in terms of mortality reduction in patients with stable CAD.

Prognostic value of access and non-access sites bleeding after percutaneous coronary intervention.

BACKGROUND: Little is known about the impact of bleeding site on mortality after percutaneous coronary intervention. The aim of this study was to assess the impact of access and non-access site bleeding within 30 days after percutaneous coronary intervention on mortality. METHODS AND RESULTS: This study represents a pooled patient-level analysis of 14 180 patients recruited in 7 randomized trials. Access and non-access site bleeding were assessed using the Bleeding Academic Research Consortium criteria. The primary outcome was 1-year mortality. Follow-up was complete in 97.5% of the patients. There were 414 deaths within the first year after percutaneous coronary intervention: 44 deaths among patients with access site bleeding, 60 deaths among patients with non-access site bleeding, and 310 deaths among patients without bleeding (Kaplan-Meier estimates of mortality, 4.5%, 10.0%, and 2.5%, respectively; adjusted hazard ratio, 1.72 [95% confidence interval, 1.19-2.47] for access site bleeding versus no bleeding; hazard ratio, 2.78 [2.00-3.86] for non-access site versus no bleeding). The inclusion of non-access site bleeding (the absolute and relative integrated discrimination improvement, 0.005 and 8.9%; P=0.031) but not of access site bleeding (the absolute and relative integrated discrimination improvement, 0.0015 and 2.7%; P=0.084) was associated with an improvement of the discriminatory power of multivariable model for mortality prediction. CONCLUSIONS: Both access and non-access site bleeding events occurring within 30 days of a percutaneous coronary intervention are independently associated with an increased risk of 1-year mortality. Non-access site bleeding is a stronger correlate of mortality than access site bleeding, and it improves the discriminatory power of models for mortality prediction.

Fibrin sealants in orthopaedic surgery: practical experiences derived from use of QUIXIL® in total knee arthroplasty.

BACKGROUND: Total knee arthroplasty is associated with a significant postoperative blood loss even without any form of perioperative anticoagulation. METHODS: The potential role of QUIXIL(®), a fibrin sealant used in orthopaedic surgery to control blood loss and avoid blood transfusions in patients undergoing total knee arthroplasty was evaluated in a prospective randomized trial with twenty-four patients diagnosed with primary osteoarthritis of the knee. RESULTS: Results showed that application of 2 ml QUIXIL(®) adds costs to treatment without reducing the number of transfused red blood cell counts and postoperative haemoglobin loss. However, significant lower levels of postoperative fluid loss (P = 0.026) was detected in QUIXIL(®) treated patients. CONCLUSION: Regarding cost effectiveness and benefit no indication for the use of 2 ml QUIXIL(®) fibrin sealant in standard knee arthroplasty could be proofed statistically.