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.

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.

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.

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.

WITHDRAWN: Cognition and Dementia Related Adverse Effects with Sacubitril-Valsartan: Analysis of the FDA Adverse Event Report System Database.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.cardfail.2018.04.009. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Gender Differences in Efficacy and Safety of Direct Oral Anticoagulants in Atrial Fibrillation: Systematic Review and Network Meta-analysis.

BACKGROUND: Studies indicate that women with atrial fibrillation (AF) are less likely to receive anticoagulants despite their higher risk of stroke compared with men. OBJECTIVE: To evaluate whether the efficacy and safety of direct oral anticoagulants (DOACs) differ in women with AF as compared with men. Our secondary aim was to examine gender differences regarding the safety and efficacy of specific DOACs. DATA SOURCES: MEDLINE, EMBASE, Cochrane, and ClinicalTrials.gov were searched through March 2017. STUDY SELECTION AND DATA EXTRACTION: Randomized clinical trials that reported on major bleeding and stroke with DOACs in women and men with AF were included. Meta-analysis and network meta-analysis was performed. DATA SYNTHESIS: Five trials met the inclusion criteria. Among 66 389 patients, 37.8% were women. Women treated with DOACs were at higher risk of stroke and systemic embolism compared with men (RR = 1.19; 95% CI = 1.04-1.35; I2 = 10%) but there was a significantly lower risk of major bleeding in women compared with men (RR = 0.86; 95% CI = 0.78-0.94; I2 = 0%). Network meta-analyses suggested differences between various DOACs in men and women. LIMITATIONS: Patient-level data enabling control for differences in baseline risk and head-to-head comparisons between DOACs were not available. Relevance to Patient Care and Clinical Practice: Undertreatment with DOACs among women cannot be justified. CONCLUSION: Women treated with DOACs had a lower rate of major bleeding and higher rate of stroke and systemic emboli compared with men. Further investigation of DOACs, including differences between the DOACs in specific populations is warranted.

Direct-acting oral anticoagulant drug level monitoring in clinical patient management.

The role of drug-level monitoring among patients using direct-acting oral anticoagulant (DOAC) is unclear. We aimed to investigate its 'real-life' utilization and effect on clinical management. A review of records of patients who underwent DOAC level testing during 2013-2017. Overall, 212 patients (median age 77 years) underwent 292 DOAC measurements [apixaban (n = 147), rivaroxaban (n = 102), dabigatran (n = 43)]. Monitoring volume increased by 460% during study period. DOAC level testing was performed during routine follow-up in 51 (17.5%) cases, whereas the remaining 241 (82.5%) measurements were performed due to selected clinical circumstances, most commonly: bleeding (n = 60), perioperative status (n = 45), breakthrough thrombosis (n = 37) and renal failure (n = 35). Drug levels were within the expected range in 210 (71.9%), above the expected range in 62 (21.2%) and lower than expected range in 20 (6.8%). In multivariate analysis, older age (P = 0.005), lower glomerular filtration rate (P = 0.001) and lower body mass index (P = 0.006) were associated with DOAC levels above the expected range. Clinical decisions were affected by DOAC monitoring following most (140/241, 58.1%) measurements for which we identified an indication for testing; yet only rarely when monitoring was performed during routine follow-up (7.8%, 4/51) (P < 0.0001). While no benefit of routine DOAC monitoring was observed, drug level measurement has an important role in the management of patients in selected circumstances. Age, body weight and creatinine clearance were found to be significant predictors of drug levels. Future studies are warranted to establish associations between drug levels and outcomes, and better delineate the role of DOAC monitoring.

The effect of bariatric surgery on direct-acting oral anticoagulant drug levels.

OBJECTIVE: To determine direct-acting oral anticoagulant (DOAC) blood levels in post-bariatric surgery (BS) patients treated with long-term anticoagulation therapy. METHODS: We identified from medical records patients who underwent BS during 2005-2016 and who were treated with DOACs. We offered testing DOAC blood levels to these patients and to age, sex, body mass index, and serum creatinine-matched individuals treated by DOACs who did not undergo BS. RESULTS: Overall, 36 individuals were enrolled, 18 post-BS patients and 18 control subjects. Of the post-BS patients, 12 underwent laparoscopic sleeve gastrectomy, 4 laparoscopic adjustable gastric banding and 2 laparoscopic Roux-en-Y gastric bypass surgery. Median time lapsed from surgery until study inclusion was 4.9years. Five post-BS patients had peak drug levels below expected levels compared to none of the control subjects (P=0.05). For patients who used apixaban (n=9) and dabigatran (n=2), peak drug levels were within the expected range. In contrast, for the 7 patients who used rivaroxaban, levels were below the expected range in 5, including all four who underwent sleeve gastrectomy and one following adjustable gastric banding. Peak rivaroxaban levels were significantly lower in the post-BS than the control group (P=0.02). CONCLUSION: This preliminary study suggests that all DOACs, particularly rivaroxaban, be cautiously used following BS, if used at all. Given that vitamin-K antagonists can be easily monitored, they may be a better choice, until more data on DOAC use in this patient population are available.

Role of vasopressin and terlipressin in refractory shock compared to conventional therapy in the neonatal and pediatric population: a systematic review, meta-analysis, and trial sequential analysis.

BACKGROUND: Vasopressin (AVP) and terlipressin (TP) have been used as last-line therapy in refractory shock in children. However, the efficacy and safety profiles of AVP and TP have not been determined in pediatric refractory shock of different origins. We aimed to assess the efficacy and safety of the addition of AVP/TP therapy in pediatric refractory shock of all causes compared to conventional therapy with fluid resuscitation and vasopressor and inotropic therapy. METHODS: We conducted a systematic review, meta-analysis, and trial sequential analysis (TSA) comparing AVP and TP to conventional therapy. MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched up to February 2016. The systematic review included all reports of AVP/TP use in the pediatric population. Reports of clinical trials were pooled using random-effects models and TSA. Main outcomes were mortality and tissue ischemia. RESULTS: Three randomized controlled trials and five "before-and-after clinical" trials (without comparator) met the inclusion criteria. Among 224 neonates and children (aged 0 to 18 years) with refractory shock, 152 received therapy with AVP or TP. Pooled analyses showed no association between AVP/TP treatment and mortality (relative risk (RR),1.19; 95% confidence interval (CI), 0.71-2.00), length of stay in the pediatric intensive care unit (PICU) (mean difference (MD), -3.58 days; 95% CI, -9.05 to 1.83), and tissue ischemia (RR, 1.48; 95% CI, 0.47-4.62). In TSA, no significant effect on mortality and risk for developing tissue ischemia was observed with AVP/TP therapy. CONCLUSION: Our results emphasize the lack of observed benefit for AVP/TP in terms of mortality and length of stay in the PICU, and suggest an increased risk for ischemic events. Our TSA suggests that further large studies are necessary to demonstrate and establish benefits of AVP/TP in children. PROSPERO registry: CRD42016035872.

Major Bleeding and Hemorrhagic Stroke With Direct Oral Anticoagulants in Patients With Renal Failure: Systematic Review and Meta-Analysis of Randomized Trials.

BACKGROUND: Direct oral anticoagulants (DOACs) are used as an alternative for traditional antithrombotic therapy. However, the safety profile of DOACs in patients with renal failure (RF) has not been determined. METHODS: A systematic review was performed assessing the reported safety of DOACs compared with vitamin K antagonists (VKAs) in patients with RF and estimated creatinine clearance (eCrCL) < 50 mL/min and eCrCL 50 to 80 mL/min. MEDLINE, EMBASE, Cochrane, and the Clinical Trials Registry (ClinicalTrials.gov) were searched for randomized clinical trials up to November 2015. The data were pooled by using both traditional frequentist and Bayesian random effects models. RESULTS: Nine trials met the inclusion criteria. Among 94,897 participants, 54,667 (58%) had RF. Compared with VKAs, DOACs were associated with a significantly decreased risk for major bleeding in patients with eCrCL 50 to 80 mL/min (risk ratio, 0.87 [95% CI, 0.81-0.93]) and a nonsignificant decrease in the risk for major bleeding in patients with eCrCL < 50 mL/min (risk ratio, 0.83 [95% CI, 0.68-1.02]); there was evidence of significant heterogeneity. Indirect comparisons, using Bayesian network analysis, indicated that apixaban was associated with a decreased rate of major bleeding compared with other DOACs in patients with eCrCL < 50 mL/min. DOACs were associated with a significant decrease in the risk for hemorrhagic stroke compared with VKAs in patients with eCrCL < 50 mL/min and 50 to 80 mL/min. CONCLUSIONS: As a class, DOACs are associated with a reduced risk for hemorrhagic stroke compared with VKAs in patients with RF. However, DOACs may differ from each other in their relative risk for major bleeding in patients with eCrCL < 50 mL/min. TRIAL REGISTRY: PROSPERO registry; No.: CRD42014013730; URL: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014013730.