Planned oocyte cryopreservation: a systematic review and meta-regression analysis.

BACKGROUND: Awareness of the age-related decline in fertility potential has increased the popularity of planned oocyte cryopreservation (POC). However, data regarding outcomes of POC, including rates of women returning to thaw oocytes, as well as pregnancy and live birth rates, are scarce and based mostly on small case series. OBJECTIVE AND RATIONALE: POC was defined as cryopreservation exclusively for prevention of future age-related fertility loss. The primary outcome was live birth rate per patient. The secondary outcomes included the return to thaw rate and laboratory outcomes. A meta-regression analysis examining the association between live birth and age above 40 or below 35 was conducted. SEARCH METHODS: We conducted a systematic database search from inception to August 2022. The search included PubMed (MEDLINE) and EMBASE. Our search strategies employed a combination of index terms (Mesh) and free text words to compile relevant concepts. The systematic review and meta-regression were undertaken following registration of systematic review (PROSPERO registration number CRD42022361791) and were reported following guidelines of Preferred Reporting Items for Systematic Review and Meta-Analyses 2020 (PRISMA 2020). OUTCOMES: The database search yielded 3847 records. After the selection process, 10 studies, conducted from 1999 to 2020, were included. Overall, 8750 women underwent POC, with a mean cryopreservation age of 37.2 (±0.8). Of those, 1517 women returned to use their oocytes with a return rate of 11.1% (± 4.7%). The mean age at the time of cryopreservation for women who returned to use their oocytes was 38.1 (±0.4), with an average of 12.6 (±3.6) cryopreserved oocytes per woman. In a meta-analysis, the oocyte survival rate was 78.5% with a 95% CI of 0.74-0.83 (I2 = 93%). The live birth rate per patient was 28% with a 95% CI of 0.24-0.33 (I2 = 92%). Overall, 447 live births were reported. In a sub-group analysis, women who underwent cryopreservation at age ≥40 achieved a live birth rate per patient of 19% (95% CI 0.13-0.29, I2 = 6%), while women aged ≤35 years old or younger had a higher live birth rate per patient of 52% (95% CI 0.41-0.63, I2 = 7%). WIDER IMPLICATIONS: POC emerges as a feasible option for women aiming to improve their chances of conceiving at a later reproductive age. Nonetheless, it must be acknowledged that the overall success rates of POC are limited and that the likelihood of successful live birth declines as the age at cryopreservation rises. With increasing interest in POC, the collation of comprehensive and high-quality data is imperative to clearly define the outcomes for various age groups. REGISTRATION NUMBER: CRD42022361791.

The Effect of Levetiracetam Compared with Enzyme-Inducing Antiseizure Medications on Apixaban and Rivaroxaban Peak Plasma Concentrations.

BACKGROUND AND OBJECTIVE: Post-stroke epilepsy represents an important clinical challenge as it often requires both treatment with direct oral anticoagulants (DOACs) and antiseizure medications (ASMs). Levetiracetam (LEV), an ASM not known to induce metabolizing enzymes, has been suggested as a safer alternative to enzyme-inducing (EI)-ASMs in patients treated with DOACs; however, current clinical guidelines suggest caution when LEV is used with DOACs because of possible P-glycoprotein induction and competition (based on preclinical studies). We investigated whether LEV affects apixaban and rivaroxaban concentrations compared with two control groups: (a) patients treated with EI-ASMs and (b) patients not treated with any ASM. METHODS: In this retrospective observational study, we monitored apixaban and rivaroxaban peak plasma concentrations (Cmax) in 203 patients treated with LEV (n = 28) and with EI-ASM (n = 33), and in patients not treated with any ASM (n = 142). Enzyme-inducing ASMs included carbamazepine, phenytoin, phenobarbital, primidone, and oxcarbazepine. We collected clinical and laboratory data for analysis, and DOAC Cmax of patients taking LEV were compared with the other two groups. RESULTS: In 203 patients, 55% were female and the mean age was 78 ± 0.8 years. One hundred and eighty-six patients received apixaban and 17 patients received rivaroxaban. The proportion of patients with DOAC Cmax below their therapeutic range was 7.1% in the LEV group, 10.6% in the non-ASM group, and 36.4% in the EI-ASM group (p < 0.001). The odds of having DOAC Cmax below the therapeutic range (compared with control groups) was not significantly different in patients taking LEV (adjusted odds ratio 0.70, 95% confidence interval 0.19-2.67, p = 0.61), but it was 12.7-fold higher in patients taking EI-ASM (p < 0.001). In an analysis in patients treated with apixaban, there was no difference in apixaban Cmax between patients treated with LEV and non-ASM controls, and LEV clinical use was not associated with variability in apixaban Cmax in a multivariate linear regression. CONCLUSIONS: In this study, we show that unlike EI-ASMs, LEV clinical use was not significantly associated with lower apixaban Cmax and was similar to that in patients not treated with any ASM. Our findings suggest that the combination of LEV with apixaban and rivaroxaban may not be associated with decreased apixaban and rivaroxaban Cmax. Therefore, prospective controlled studies are required to examine the possible non-pharmacokinetic mechanism of the effect of the LEV-apixaban or LEV-rivaroxaban combination on patients' outcomes.

Catheter-directed thrombolysis compared with systemic thrombolysis and anticoagulation in patients with intermediate- or high-risk pulmonary embolism: systematic review and network meta-analysis.

BACKGROUND: Therapeutic options for intermediate- or high-risk pulmonary embolism (PE) include anticoagulation, systemic thrombolysis and catheter-directed thrombolysis (CDT); however, the role of CDT remains controversial. We sought to compare the efficacy and safety of CDT with other therapeutic options using network meta-analysis. METHODS: We searched PubMed (MEDLINE), Embase, ClinicalTrials.gov and Cochrane Library from inception to Oct. 18, 2022. We included randomized controlled trials and observational studies that compared therapeutic options for PE, including anticoagulation, systemic thrombolysis and CDT among patients with intermediate- or high-risk PE. The efficacy outcome was in-hospital death. Safety outcomes included major bleeding, intracerebral hemorrhage and minor bleeding. RESULTS: We included data from 44 studies, representing 20 006 patients. Compared with systemic thrombolysis, CDT was associated with a decreased risk of death (odd ratio [OR] 0.43, 95% confidence interval [CI] 0.32-0.57), intracerebral hemorrhage (OR 0.44, 95% CI 0.29-0.64), major bleeding (OR 0.61, 95% CI 0.53-0.70) and blood transfusion (OR 0.46, 95% CI 0.28-0.77). However, no difference in minor bleeding was observed between the 2 therapeutic options (OR 1.11, 95% CI 0.66-1.87). Compared with anticoagulation, CDT was also associated with decreased risk of death (OR 0.36, 95% CI 0.25-0.52), with no increased risk of intracerebral hemorrhage (OR 1.33, 95% CI 0.63-2.79) or major bleeding (OR 1.24, 95% CI 0.88-1.75). INTERPRETATION: With moderate certainty of evidence, the risk of death and major bleeding complications was lower with CDT than with systemic thrombolysis. Compared with anticoagulation, CDT was associated with a probable lower risk of death and a similar risk of intracerebral hemorrhage, with moderate certainty of evidence. Although these findings are largely based on observational data, CDT may be considered as a first-line therapy in patients with intermediate- or high-risk PE. PROTOCOL REGISTRATION: PROSPERO - CRD42020182163.

Implantable cardioverter defibrillator for primary prevention in patients with non-ischemic cardiomyopathy in the era of novel therapeutic agents- meta-analysis.

Background: Evidence regarding the mortality benefit of implantable cardioverter defibrillator (ICD) non-ischemic dilated cardiomyopathy (NIDCM) is inconsistent. The most recent randomized study, the DANISH trial, did not find improved outcomes with ICD. However, based on previous studies and meta-analyses, current guidelines still highly recommend ICD implantation in NIDCM patients. The introduction of novel medications for heart failure improved the clinical outcome dramatically. We aimed in this study to evaluate the effect of Angiotensin Receptor-Neprilysin Inhibitors (ARNi) and sodium-glucose transport protein 2 inhibitors (SGLT2i) on the mortality benefit of ICD in NIDCM. Methods: We used a previous metanalysis algorithm and added an updated comprehensive literature search in PubMed for randomized control trials that examined the mortality benefit of ICD in NIDCM vs. optimal medical treatment. The primary outcome included death from any cause. We did a meta-regression analysis to search for a single independent factor affecting mortality. Using previous data, we evaluated the theoretical effect of ICD implementation on patients treated with SGLT2 inhibitors and ARNi. Results: No new articles were added to the results of the previous meta-analysis. 2,622 patients with NIDCM from 5 cohort studies published between 2002 and 2016 were included in the analysis. 50% of them underwent ICD implantation for primary prevention of sudden cardiac death, and 50% did not. ICD was associated with a significantly decreased risk for death from any cause compared to control (OR = 0.79, 95%CI: 0.66-0.95, p = 0.01, I2 = 0%). The theoretical addition of ARNi and the SGLT2 inhibitor dapagliflozin did not change the significant mortality effect of ICD (OR = 0.82, 95%CI: 0.7-0.9, p = 0.001, I2 = 0%) and (OR = 0.82, 95%CI: 0.7-0.9, p = 0.001, I2 = 0%). A meta-regression revealed no association between death from any cause and left bundle branch block (LBBB), use of amiodarone, use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers, year initiated enrollment, and the year ended enrollment (R2 = 0.0). Conclusion: In patients with NIDCM, the addition of ARNi and SGLT2i did not affect the mortality advantages of ICD for primary prevention. PROSPERO registry number: https://www.crd.york.ac.uk/prospero/, identifier: CRD42023403210.

Pravastatin and placental insufficiency associated disorders: A systematic review and meta-analysis.

Background: Uteroplacental insufficiency associated disorders, such as preeclampsia, fetal growth restriction and obstetrical antiphospholipid syndrome, share pathophysiology and risk factors with cardiovascular diseases treated with statins. Objective: To evaluate pregnancy outcomes among women with uteroplacental insufficiency disorders who were treated with statins. Search Strategy: Electronic databases were searched from inception to January 2022 Selection Criteria: Cohort studies and randomized controlled trials. Data collection and analysis: Pooled odds ratios were calculated using a random-effects model; meta-regression was utilized when applicable. Main Results: The analysis included ten studies describing 1,391 women with uteroplacental insufficiency disorders: 703 treated with pravastatin and 688 not treated with statins. Women treated with pravastatin demonstrated significant prolongation of pregnancy (mean difference 0.44 weeks, 95%CI:0.01-0.87, p = 0.04, I2 = 96%) and less neonatal intensive care unit admissions (OR = 0.42, 95%CI: 0.23-0.75, p = 0.004, I2 = 25%). In subgroup analysis, prolongation of pregnancy from study entry to delivery was statistically significant in cohort studies (mean difference 8.93 weeks, 95%CI:4.22-13.95, p = 0.00) but not in randomized control studies. Trends were observed toward a decrease in preeclampsia diagnoses (OR = 0.54, 95%CI:0.27-1.09, p = 0.09, I = 44%), perinatal death (OR = 0.32, 95%CI:0.09-1.13, p = 0.08, I2 = 54%) and an increase in birth weight (mean difference = 102 g, 95%CI: -14-212, p = 0.08, I2 = 96%). A meta-regression analysis demonstrated an association between earlier gestational age at initiation of treatment and a lower risk of preeclampsia development (R2 = 1). Conclusion: Pravastatin treatment prolonged pregnancy duration and improved associated obstetrical outcomes in pregnancies complicated with uteroplacental insufficiency disorders in cohort studies. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/ identifier CRD42020165804 17/2/2020.

The effect of statins exposure during pregnancy on congenital anomalies and spontaneous abortions: A systematic review and meta-analysis.

Objective: To assess the effect of statin exposure during pregnancy on congenital anomalies and spontaneous abortions. Data sources: Electronic databases were searched from inception to January 2022. Study Eligibility Criteria: Cohort studies and randomized controlled trials (RCTs) evaluate the effect of treatment with statins on congenital anomalies in general and cardiac malformations in particular. Studies evaluating spontaneous abortions were included as a secondary outcome. Study appraisal and synthesis methods: Pooled odds ratio was calculated using a random-effects model and meta-regression was utilized when applicable. Results: Twelve cohort studies and RCTs were included in the analysis. Pregnancy outcomes of 2,447 women that received statins during pregnancy were compared to 897,280 pregnant women who did not. Treatment with statins was not associated with a higher risk of overall congenital anomalies (Odd Ratio = 1.1, CI (0.9-1.3), p = 0.33, I2 = 0%). Yet, cardiac malformations were more prevalent among neonates born to statins users (OR = 1.4, CI (1.1-1.8), p = 0.02, I2 = 0%). The risk was higher when exposure occurred during the first trimester. This finding was statistically significant in cohort studies, but not in RCTs. Statin treatment was also associated with a higher rate of spontaneous abortions (OR = 1.5, CI (1.1-2.0), p = 0.005, I2 = 0%). In meta-regression analysis, no significant association between lipophilic statins and the rate of congenital anomalies was found. Conclusion: Overall, treatment with statins during pregnancy was not associated with an increased risk of congenital anomalies. A slight risk elevation for cardiac malformation and spontaneous abortions was seen in cohort studies but not in RCTs. Systematic Review Registration: clinicaltrials.gov, identifier [CRD42020165804 17/2/2020] The meta-analysis was presented online at 42nd annual meeting of SMFM. January 31-5 February 2022.

Calcium Channel Blocker Use and the Risk for Breast Cancer: A Population-Based Nested Case-Control Study.

We investigated whether long-term exposure to calcium channel blockers (CCBs) is associated with an increased risk of breast cancer (BCa). We designed a nested case-control study based on data from the Clalit electronic database, the largest Israeli Health Services organization. All newly diagnosed breast cancer (BCa) cases were selected from a cohort of patients with hypertension. Ten controls were matched for each BCa case. The odds ratios (ORs) of BCa among CCBs users were calculated using multivariate conditional logistic regression analyses. A total of 4875 patients with newly diagnosed BCa were identified from the cohort with a median follow-up of 5.15 years. The exposure to CCBs was not associated with an increased risk of BCa (OR = 0.98; 95% CI, 0.92-1.04). Additionally, there was no association between long-term exposure to CCBs (above eight years) and increased BCa risk (OR = 0.91; 95% CI, 0.67-1.21). Higher cumulative doses of CCBs were not associated with an elevated risk of BCa (OR = 0.997; 95% CI, 0.962-1.034, calculated per 1000 DDD). Based on this large population-based study, long-term exposure to CCBs was not associated with an increased risk of BCa. Considering that CCBs are widely used medications, our results provide important safety information on a population level, especially for patients with an increased risk of BCa.

Severe Acute Myocarditis after the Third (Booster) Dose of mRNA COVID-19 Vaccination.

Vaccination with mRNA vaccines against coronavirus disease 2019 (COVID-19) has been associated with a risk of developing myocarditis and pericarditis, with an estimated standardized incidence ratio of myocarditis being 5.34 (95% CI, 4.48 to 6.40) as compared to the expected incidence based on historical data according to a large national study in Israel. Most cases of myocarditis in vaccine recipients occur in young males, particularly following the second dose, and the presentation is usually mild. Recently, the third (booster) dose has been shown to reduce confirmed infections and severe illness even against common variants of the virus. In Israel, over 4.4 million citizens (more than 45% of the population) have been vaccinated with the third dose of Pfizer-BioNTech vaccine BNT162b2. Herein, we report the first case of a histologically confirmed severe myocarditis following the third dose of BNT162b2 COVID-19 vaccine.

Efficacy and safety outcomes of long-term anti-thrombotic treatment of chronic coronary artery disease: A systematic review and network meta-analysis.

Background: Clopidogrel, prasugrel, ticagrelor, and low-dose rivaroxaban are all optional strategies in conjunction with aspirin for long-term treatment of chronic coronary artery disease. The aim of this research was to assess the efficacy and safety of long-term anti-thrombotic treatment of chronic coronary heart disease. Methods: PubMed (MEDLINE), Embase, Clinical Trials Registry ClinicalTrials.gov, and The Cochrane Library were searched through November 2021, to identify randomized controlled trials that compared long term anti-thrombotic therapy for coronary heart disease. Data were extracted to assess eligibility by two independent reviewers. Random-effects meta-analysis was used to pool results. Results: Eleven randomized controlled trials were included (88,462 patients). In a network meta-analysis, the rivaroxaban compared to the clopidogrel regimen showed lower relative risks (RRs) for death of any cause (0.71; 95% confidence interval [CI], 0.52-0.96), major adverse cardiac events (MACE) (0.73; 95% CI, 0.57-0.93), and cerebrovascular events (0.48; 95% CI, 0.30-0.78). The RR of cerebrovascular events was also lower for the rivaroxaban compared to the ticagrelor 60 mg regimen (0.72; 95% CI, 0.52-0.99). For the prasugrel regimen, the RRs were lower of myocardial infarction incidence versus all extended strategies: clopidogrel plus aspirin (0.76; 95% CI, 0.58-0.99), rivaroxaban (0.60; 95% CI, 0.38-0.93), ticagrelor 60 mg (0.61; 95% CI, 0.42-0.89), and ticagrelor 90 mg (0.63; 95% CI, 0.41-0.97). None of the dual strategies were associated with differences in major bleeding compared to the prasugrel regimen. Conclusions and relevance: The rivaroxaban regimen appeared to be the preferred long-term anti-thrombotic regimen in preventing all-cause mortality. Our available results tend to support the efficacy of extended anti-thrombotic therapy consisting of prasugrel in lowering MI incidence compared to the other strategies, without increased risk of bleeding. However, additional large-scale direct clinical trials are needed to further determine the adequate long-term anti-thrombotic regimens for treating chronic coronary syndrome. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020186583, identifier CRD42020186583.

Comparing the clinical efficacy of COVID-19 vaccines: a systematic review and network meta-analysis.

New Coronavirus Disease 2019 (COVID-19) vaccines are available to prevent the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. We compared the efficacy of new COVID-19 vaccines to prevent symptomatic and severe disease in the adult population and to prevent symptomatic COVID-19 among the elderly. Leading medical databases were searched until August 30, 2021. Published phase 3 randomized controlled trials (RCTs) evaluated efficacy of the vaccine to prevent symptomatic and sever COVID-19 in adults were included. Two reviewers independently evaluated the literature search results and independently extracted summary data. The risk of bias was evaluated using the Cochrane Risk of Bias Assessment Tool. We performed a network meta-analysis (NMA) according to PRISMA-NMA 2015 to pool indirect comparisons between different vaccines regarding their relative efficacy. The primary outcomes were the efficacy of the vaccine against symptomatic COVID-19 in adults (PROSPERO registration number: CRD42021235364). Above 200,000 adult participants from eight phase 3 RCTs were included in NMA, of whom 52% received the intervention (active COVID-19 vaccine). While each of nine vaccines was tested in the unique clinical trial as compared to control, based on indirect comparison, BNT162b2 and mRNA-1273 vaccines were ranked with the highest probability of efficacy against symptomatic COVID-19 (P-scores 0.952 and 0.843, respectively), followed by Gam-COVID-Vac (P-score 0.782), NVX-CoV23730 (P-score 0.700), CoronaVac (P-score 0.570), BN02 (P-score 0.428), WIV04 (P-score 0.327), and Ad26.COV2.S (P-score 0.198). No statistically significant difference was seen in the ability of the vaccines to prevent symptomatic disease in the elderly population. No vaccine was statistically significantly associated with a decreased risk for severe COVID-19 than other vaccines, although mRNA-1273 and Gam-COVID-Vac have the highest P-scores (0.899 and 0.816, respectively), indicating greater protection against severe disease than other vaccines. In our indirect comparison, the BNT162b2 and mRNA-1273 vaccines, which use mRNA technology, were associated with the highest efficacy to prevent symptomatic COVID-19 compared to other vaccines. This finding may have importance when deciding which vaccine to use, together with other important factors as availability of the vaccines, costs, logistics, side effects, and patient acceptability.

Prescribing Errors With Direct Oral Anticoagulants and Their Impact on the Risk of Bleeding in Patients With Atrial Fibrillation.

INTRODUCTION: Anticoagulants are associated with significant harm when used in error, but there are limited data on potential harm of inappropriate treatment with direct oral anticoagulants (DOACs). We conducted a matched case-control study among atrial fibrillation (AF) patients admitting the hospital with a chronic treatment with DOACs, in order to assess factors associated with the risk of major bleeding. METHODS: Patient data were documented using hospital's computerized provider order entry system. Patients identified with major bleeding were defined as cases and were matched with controls based on the duration of treatment with DOACs and number of chronic medications. Appropriateness of prescribing was assessed based on the relevant clinical guidelines. Conditional logistic regression was used to evaluate the potential impact of safety-relevant prescribing errors with DOACs on major bleeding. RESULTS: A total number of 509 eligible admissions were detected during the study period, including 64 cases of major bleeding and 445 controls. The prevalence of prescribing errors with DOACs was 33%. Most prevalent prescribing errors with DOACs were "drug dose too low" (16%) and "non-recommended combination of drugs" (11%). Safety-relevant prescribing errors with DOACs were associated with major bleeding [adjusted odds ratio (aOR) 2.17, 95% confidence interval (CI) 1.14-4.12]. CONCLUSION: Prescribers should be aware of the potential negative impact of prescribing errors with DOACs and understand the importance of proper prescribing and regular follow-up.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk for neurocognitive adverse events: A systematic review, meta-analysis and meta-regression.

BACKGROUND: It has been suggested that lipid lowering therapy causes impaired cognitive changes. The association between the use of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk of neurocognitive adverse events remains unclear. This meta-analysis aims to assess neurocognitive safety of PCSK9 inhibitors in randomized controlled trials (RCTs). METHODS AND RESULTS: The research was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PubMed (MEDLINE), Embase and Cochrane library were searched through September 2019. Selection criteria included RCTs that addressed to neurocognitive adverse events of participants using Alirocumab, Evolocumab or Bococizumab, with a follow up duration of at least 6 months. The search results were screened by two independent reviewers. Safety data from included papers were extracted. Random effects meta-analysis was used to pool results, and meta-regression was utilized when applicable. Twenty-one studies were included. Among 59,733 patients, 31,611 were treated with PCSK9 inhibitors. The follow-up period ranged from 24 weeks to 48 months. No significant difference in the incidence of neurocognitive adverse effects between the groups was identified (RR = 1.01, 95% CI: 0.86-1.19, I2 = 3%). Similar results were seen in subgroup analysis for each of the medications (alirocumab- RR = 0.88, 95% CI: 0.72-1.08, I2 = 0%, evolocumab- RR = 1.42, 95% CI: 0.74-2.73, I2 = 55%). A meta-regression analysis for evolocumab revealed that prolonged study duration was associated with decreased risk for neurocognitive adverse events (ßweek = -0.0037, p-value = 0.03). CONCLUSIONS: Pooled results of our meta-analysis and meta-regression show that exposure to PCSK9 inhibitors is not associated with an increased risk of neurocognitive adverse effects.

Effect of Enzyme-Inducing Antiseizure Medications on the Risk of Sub-Therapeutic Concentrations of Direct Oral Anticoagulants: A Retrospective Cohort Study.

BACKGROUND: Stroke and thromboembolic events occurring among patients taking direct oral anticoagulants (DOACs) have been associated with low concentrations of DOACs. Enzyme-inducing antiseizure medications (EI-ASMs) are associated with enhanced cytochrome-P450-mediated metabolism and enhanced P-glycoprotein-mediated transport. OBJECTIVE: The aim of this study was to evaluate the effect of concomitant EI-ASM use on DOAC peak concentrations in patients treated in clinical care. METHODS: We performed a retrospective cohort study of patients treated with DOACs for atrial fibrillation and venous thromboembolic disease in an academic general hospital. In total, 307 patients treated with DOACs between August 2015 and January 2020 were reviewed. Clinical characteristics and peak DOAC plasma concentrations of patients co-treated with an EI-ASM were compared with those of patients not treated with an EI-ASM. An apixaban dose score (ADS) was defined to account for apixaban dosage and the number of apixaban dose-reduction criteria. RESULTS: In total, 177 peak DOAC plasma concentrations (including apixaban, rivaroxaban, and dabigatran) from 131 patients were measured, including 24 patients co-treated with an EI-ASM and 107 controls not treated with an EI-ASM. The proportion of patients with DOAC concentrations below the expected range was significantly higher among EI-ASM users than among patients not taking an EI-ASM (37.5 vs. 9.3%, respectively; p = 0.0004; odds ratio 5.82; 95% confidence interval [CI] 2.03-16.66). Most of these patients were treated with apixaban (85%); however, sensitivity analysis results were also significant (p = 0.031) for patients with non-apixaban DOACs. In patients co-treated with apixaban and an EI-ASM, median apixaban peak concentration was 106 ng/mL (interquartile range [IQR] 71-181) compared with 150 ng/mL (IQR 94-222) in controls (p = 0.019). In multivariable analysis, EI-ASM use was associated with 6.26-fold increased odds for apixaban concentration below the expected range (95% CI 2.19-17.90; p = 0.001). Apixaban concentrations were significantly associated with EI-ASM use, moderate enzyme inhibitor use, and ADS. CONCLUSIONS: Concurrent EI-ASM and DOAC use presents a possible risk for DOAC concentrations below the expected range. The clinical significance of the interaction is currently unclear.

Anti-Remodeling Cardiac Therapy in Patients With Duchenne Muscular Dystrophy, Meta-Analysis Study.

Background: Almost all Duchenne muscular dystrophy (DMD) patients that reach their 30s present cardiomyopathy. As a result, this population remains under-treated. There is no sufficient proof of the efficacy of anti-remodeling cardiac therapy for DMD cardiomyopathy (DMDCM). We aim to assess the efficacy of anti-remodeling cardiac therapy for DMDCM by using meta-analysis. Methods: PubMed (MEDLINE), Embase, and Cochrane library were searched through January 2021. Randomized control trials, case-control studies, and observational studies that reported assessments of cardiovascular outcomes and death of participants using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, mineralocorticoid-receptor antagonists and Ivabradine, were included. The primary outcome was total mortality. Secondary outcomes included changes in left ventricular ejection fraction (LVEF), serum natriuretic peptide levels (BNP), and heart rate (HR). Data were extracted for eligibility by two independent reviewers. Random-effects meta-analysis was used to pool results. Results: Twelve studies with 439 patients were included in our meta-analysis. Treated patients have lower HR, mean difference of -17 beats per minute (CI [-25]-[-9], p < 0.01). The LVEF was improved in treated patients, with a mean difference of LVEF of 3.77% (CI 0.44-7.12, p < 0.03). Although mortality rates did not reach statistical significance there was a trend for total mortality reduction (hazard ratio 0.36, CI (0.1-1.25), p = 0.107) and for BNP reduction (SSMD: 0.141, CI ([-0.19]-[0.47]), p = 0.3). Conclusion: Pharmacologic treatment for DMDCM patients is associated with decreased HR and improved LVEF. Therefore, DMDCM patients may benefit from implementing guideline therapy for HF.

The effect of multidrug exposure on neurological manifestations in carbamazepine intoxication: a nested case-control study.

BACKGROUND: In acute intoxication, carbamazepine concentration above 40 mcg/ml is associated with a risk of severe neurological consequences, including depressed consciousness, respiratory depression, cardiac conduction disorders, seizures, and death. Carbamazepine intoxication is often associated with the use of concomitant medications. However, the effect of exposure to other central-nervous-system (CNS) acting medications on the neurological manifestations of carbamazepine toxicity has not been evaluated. OBJECTIVE: To examine the effect of exposure to CNS-acting medications on the neurological effects of carbamazepine toxicity. METHODS: A retrospective nested case-control study of all patients > 18 years of age, with at least one test of carbamazepine levels > 18 mcg/ml recorded at the Hadassah Hospital Central Laboratory, between the years 2004-2016. Sociodemographic and clinical data were collected from the computerized medical records, and the characteristics of patients with and without severe neurological symptoms of carbamazepine intoxication were compared. RESULTS: Eighty patients were identified. In bivariate analyses, the odds of severe neurological symptoms was higher in patients with antidepressants use (odds ratio 8.7, 95% confidence interval: 1.8-41.2, p = 0.007), benzodiazepines use (8.6, 2.0-37.1, p = 0.004), and carbamazepine concentration above 30 mcg/ml (8.1, 1.9-33.3, p = 0.004). Multivariate models demonstrated that antidepressants and benzodiazepines were associated with severe neurological manifestations during carbamazepine intoxication, independently of carbamazepine concentration over 30 mcg/ml. ICU admission was associated in multivariate analysis with antidepressants (but not benzodiazepines) use, and with carbamazepine levels > 30 mcg/ml. CONCLUSIONS: Among patients with carbamazepine intoxication, severe neurological symptoms are associated with exposure to benzodiazepines or antidepressants and with carbamazepine levels higher than 30 mcg/ml.

The cardiovascular safety of antiobesity drugs-analysis of signals in the FDA Adverse Event Report System Database.

AIMS: Over the past several decades, many antiobesity drugs have been withdrawn from the market due to unanticipated adverse events, often involving cardiotoxicity. This study aimed to evaluate the presence of cardiovascular safety signals with currently marketed antiobesity drugs. METHODS: We used the US Food and Drug Administration Adverse Event Reporting System (FAERS) database and retrieved data from January 2013 through December 2018. We performed disproportionality analyses to detect cardiovascular safety signals with three antiobesity drugs recently approved for marketing: lorcaserin, naltrexone-bupropion, phentermine, and phentermine-topiramate. Three main cardiovascular outcomes were evaluated: valvular disorders, and pulmonary hypertension (PH) and other cardiovascular events (myocardial infarction, stroke, cardiovascular death, cardiac failure, and arrhythmia). RESULTS: During the evaluated period, a total of 6,787,840 adverse event reports were submitted to FAERS. Of these, 2687 involved lorcaserin, 3960 involved phentermine/phentermine-topiramate, and 2873 involved naltrexone-bupropion. Lorcaserin was associated with a significantly greater proportion of reports of valvular disorders (ROR = 4.39; 95% CI 2.72-5.07). None of the antiobesity drugs were associated with a safety signal for valvulopathy, PH, or other cardiovascular events. CONCLUSIONS: Our analyses revealed a signal for valvular disorders with lorcaserin and did not detect a safety signal for other cardiovascular events with recently approved antiobesity drugs. Further research is needed to explore and validate this signal.

Clinical pharmacist led hospital-wide direct oral anticoagulant stewardship program.

INTRODUCTION: In the past decade, direct-acting oral anticoagulants (DOAC) have been introduced to medical practice for several indications, with a wide range of dosing regimens. As both over- and under-dosing might lead to life-threatening events, development of methods promoting safe and effective utilization of these agents is imperative. The Hadassah Clinical Pharmacy team initiated a hospital-wide program, for monitoring and promoting safe and effective prescription of DOAC during hospitalization. This study describes the types of drug related problems addressed and the program's performance in terms of consultation rates and physician acceptance. METHODS: Electronic medical records throughout the hospital were screened for DOAC orders. All DOAC orders were assessed by a clinical pharmacist for potentially-inappropriate prescribing. When potentially-inappropriate prescribing or a drug-related problem was identified, the clinical pharmacist provided consultation on management options. In specific cases, additional guidance was provided by coagulation and pharmacology specialists. Data on patient characteristics, clinical pharmacist consultations, and physician response was retrospectively retrieved for the first six months of 2017. Characteristics of patients with and without consultations were compared, consultations were categorized by the recommended management of the drug related problem, and physician acceptance rates were evaluated by category. RESULTS: During the evaluated period, 585 patients with DOAC orders were identified. Patients were evenly distributed by gender, and age averaged 78 years. Most patients received apixaban (75%) followed by rivaroxaban (14%) and dabigatran (11%), and most (63%) received "reduced dose" regimens. Clinical pharmacists provided 258 consultations for 210 patients, regarding anticoagulation management, such that more than one in three patients on DOAC had potentially inappropriate prescribing or drug related problems. Consultations included alerts regarding potentially inappropriate DOAC doses and recommendations to increase (29%) or decrease (5%) the dose, potentially inappropriate concomitant antiplatelet agents (20%), need for DOAC level monitoring (23%), and alerts regarding other drug related problems (23%). More than 70% of recommendations were accepted by the attending physician. CONCLUSION: Due to the complexity of DOAC management, potentially-inappropriate prescribing and drug related problems are common. Multidisciplinary collaborative projects including review and consultation by clinical pharmacists are an effective method of improving management of patients on DOAC. TRIAL REGISTRATION: Retrospectively registered at clinicaltrials.gov, NCT03527615 .

Appropriateness of direct oral anticoagulant dosing and its relation to drug levels in atrial fibrillation patients.

Direct oral anticoagulants (DOACs) are commonly administered at a level that is lower than that recommended by dose reduction criteria. This raises concern regarding the adequacy of anticoagulation achieved. To evaluate the relationship between inappropriate dosing and DOAC levels. Medical records of atrial fibrillation patients who underwent DOAC level testing during 2013-2017 were reviewed. The primary outcomes were drug levels under and above the expected steady-state range, and in the lowest and highest quartiles. Of 143 patients who underwent DOAC measurements, only 87 (60.8%) received the appropriate dose. Levels under the expected range and in the lowest quartile were found in 11.9% and 15.0% of patients treated with appropriate dosing compared to 21% and 41.5% of patients treated with inappropriately low dose. DOAC levels were above the expected range and in the highest quartile in 23.8% and 32.5% of patients treated with the appropriate dose compared to 7.1% and 9.4% treated with inappropriately low dose. In multivariate analysis, the administration of an appropriate DOAC dose was associated with a lower rate of DOAC in the lowest level (adjusted odds ratio [95% CI] 0.30 (0.12, 0.76), P = 0.011). On the other hand, appropriate dose was associated with drug levels in the highest quartile (odds ratio [95% CI] 3.77 (0.12, 0.76), P = 0.011). Treatment with inappropriately low DOAC dosing compared to appropriate dose is associated with lower DOAC levels. However, among those treated with appropriate dosing, a higher proportion had high DOAC levels above the expected range.

Management strategies of the interaction between direct oral anticoagulant and drug-metabolizing enzyme inducers.

Little is known regarding the management of direct oral anticoagulants (DOACs) in patients with enzyme-inducing drugs (EID). The use of EID may lead to sub-therapeutic concentrations of DOACs and to treatment failure. Thus, many patients on EIDs cannot benefit from the advantages of DOACs. This was a retrospective study, evaluating the management of hospitalized patients with DOACs. Characteristics of hospitalized patients with a prescription for DOACs, with and without EIDs, were summarized and evaluated, and management strategies addressing the potential interaction were documented, including the use of DOAC concentration monitoring. During the period evaluated, 1596 hospitalized patients with prescriptions for DOACs were identified. Most patients received apixaban (n = 1227, 77%), followed by rivaroxaban (240, 15%), and dabigatran (129, 8%). Twenty-two patients (1.4%) had concomitant EIDs. Demographic and clinical characteristics of hospitalized patients with DOACs were similar in those receiving EID and those not. Management strategies included stopping DOAC or EID (41%), and DOAC dose increase (14%). During management of these interactions, DOAC concentrations were measured for 11 of 22 patients and were below the 5th percentile of expected concentration for six of these patients. The management of patients with DOAC concentration measurement differed significantly from those without (p = 0.005), as they were much less likely to have one of the medications stopped and more often had the DOACs' dose increased. Among hospitalized patients with DOACs, EIDs are not rare. DOAC concentrations are often low in the presence of EIDs. DOAC concentration monitoring may be useful in settings requiring both DOAC and EIDs.