-
Cardiovascular Drugs and Therapy Apr 2023We aimed to determine the safety of direct oral anticoagulants (DOACs) for stroke prevention and treatment in patients with atrial fibrillation (AF). (Meta-Analysis)
Meta-Analysis Review
Severe Bleeding Risk of Direct Oral Anticoagulants Versus Vitamin K Antagonists for Stroke Prevention and Treatment in Patients with Atrial Fibrillation: A Systematic Review and Network Meta-Analysis.
PURPOSE
We aimed to determine the safety of direct oral anticoagulants (DOACs) for stroke prevention and treatment in patients with atrial fibrillation (AF).
METHODS
A systematic search of four databases (PubMed, EMBASE, Web of Science, and Cochrane Library) was performed to identify randomized controlled trials (RCTs) reporting severe bleeding events in patients taking DOACs or vitamin K antagonists (VKAs). In this frequency-based network meta-analysis, odds ratios and 95% confidence intervals were used for reporting. Based on the surface under the cumulative ranking curves (SUCRA), the relative ranking probability of each group was generated.
RESULTS
Twenty-three RCTs met the inclusion criteria, and a total of 87,616 patients were enrolled. The bleeding safety of DOACs for stroke prevention and treatment in patients with AF was ranked from highest to lowest as follows: fatal bleeding: edoxaban (SUCRA,80.2), rivaroxaban (SUCRA,68.3), apixaban (SUCRA,48.5), dabigatran (SUCRA,40.0), VKAs (SUCRA,12.9); major bleeding: dabigatran (SUCRA,74.0), apixaban (SUCRA,71.5), edoxaban (SUCRA,66.5), rivaroxaban (SUCRA,22.7), VKAs (SUCRA,15.4); gastrointestinal bleeding: apixaban (SUCRA,55.9), VKAs (SUCRA,53.7), edoxaban (SUCRA,50.5), rivaroxaban (SUCRA,50.4), dabigatran (SUCRA,39.5); intracranial hemorrhage: dabigatran (SUCRA,84.6), edoxaban (SUCRA,74.1), apixaban (SUCRA,65.8), rivaroxaban (SUCRA,24.4), VKAs (SUCRA,1.1).
CONCLUSION
Based on current evidence, for stroke prevention and treatment in patients with AF, the most safe DOAC is edoxaban in terms of fatal bleeding; dabigatran in terms of major bleeding and intracranial hemorrhage and apixaban in terms of gastrointestinal bleeding. However, given the nature of indirect comparisons, more high-quality evidence from head-to-head comparisons is still needed to confirm them.
Topics: Humans; Anticoagulants; Atrial Fibrillation; Dabigatran; Gastrointestinal Hemorrhage; Intracranial Hemorrhages; Network Meta-Analysis; Rivaroxaban; Stroke; Vitamin K; Factor Xa Inhibitors; Administration, Oral
PubMed: 34436708
DOI: 10.1007/s10557-021-07232-9 -
British Journal of Clinical Pharmacology Nov 2022Observational studies have investigated the effectiveness and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) used in nonvalvular atrial... (Meta-Analysis)
Meta-Analysis Review
Effectiveness and safety of intracranial events associated with the use of direct oral anticoagulants for atrial fibrillation: A systematic review and meta-analysis of 92 studies.
AIMS
Observational studies have investigated the effectiveness and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) used in nonvalvular atrial fibrillation. We performed a systematic review and meta-analysis assessing the risk of ischaemic stroke, thromboembolism (TE) and intracranial haemorrhage (ICH) associated with the use of DOACs and VKAs.
METHODS
Medline and Embase were systematically searched until April 2021. Observational studies were gathered and hazard ratios (HRs) with 95% confidence intervals (CI) were extracted. Subgroup analyses based on DOAC doses, history of chronic kidney disease, stroke, exposure to VKA, age and sex were performed. A random-effects model was used.
RESULTS
We included 92 studies and performed 107 comparisons. Apixaban was associated with lower risk of stroke (HR: 0.82, 95% CI: 0.68-0.99) compared to dabigatran. Rivaroxaban was associated with lower risk of stroke (HR: 0.90, 95% CI: 0.83-0.98) compared to VKA. Dabigatran (HR: 0.85, 95% CI: 0.80-0.91), rivaroxaban (HR: 0.83, 95% CI: 0.77-0.89) and apixaban (HR: 0.75, 95% CI: 0.65-0.86) were associated with lower risk for TE/stroke compared to VKA. Apixaban (HR: 1.32, 95% CI: 1.03-1.68) and rivaroxaban (HR: 1.58, 95% CI: 1.31-1.89) were associated with higher risk of ICH compared to dabigatran. Dabigatran (HR: 0.48, 95% CI: 0.44-0.52), apixaban (HR: 0.60, 95% CI: 0.49-0.73) and rivaroxaban (HR: 0.73, 95% CI: 0.65-0.81) were associated with lower risk of ICH compared to VKA.
CONCLUSION
Our study demonstrated significant differences in the risk of ischaemic stroke, TE/stroke and ICH associated with individual DOACs compared to both other DOACs and VKA.
Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Dabigatran; Humans; Intracranial Hemorrhages; Ischemic Stroke; Pyridones; Rivaroxaban; Stroke; Thromboembolism; Vitamin K
PubMed: 35853612
DOI: 10.1111/bcp.15464 -
JAMA Sep 2014Many anticoagulant strategies are available for the treatment of acute venous thromboembolism, yet little guidance exists regarding which drug is most effective and safe. (Meta-Analysis)
Meta-Analysis Review
IMPORTANCE
Many anticoagulant strategies are available for the treatment of acute venous thromboembolism, yet little guidance exists regarding which drug is most effective and safe.
OBJECTIVE
To summarize and compare the efficacy and safety outcomes associated with 8 anticoagulation options (unfractionated heparin [UFH], low-molecular-weight heparin [LMWH], or fondaparinux in combination with vitamin K antagonists); LMWH with dabigatran or edoxaban; rivaroxaban; apixaban; and LMWH alone) for treatment of venous thromboembolism.
DATA SOURCES
A systematic literature search was conducted using MEDLINE, EMBASE, and the evidence-based medicine reviews from inception through February 28, 2014.
STUDY SELECTION
Eligible studies were randomized trials reporting rates of recurrent venous thromboembolism and major bleeding in patients with acute venous thromboembolism. Of the 1197 studies identified, 45 trials including 44,989 patients were included in the analyses.
DATA EXTRACTION AND SYNTHESIS
Two reviewers independently extracted trial-level data including number of patients, duration of follow-up, and outcomes. The data were pooled using network meta-analysis.
MAIN OUTCOMES AND MEASURES
The primary clinical and safety outcomes were recurrent venous thromboembolism and major bleeding, respectively.
RESULTS
Compared with the LMWH-vitamin K antagonist combination, a treatment strategy using the UFH-vitamin K antagonist combination was associated with an increased risk of recurrent venous thromboembolism (hazard ratio [HR], 1.42; 95% credible interval [CrI], 1.15-1.79). The proportion of patients experiencing recurrent venous thromboembolism during 3 months of treatment were 1.84% (95% CrI, 1.33%-2.51%) for the UFH-vitamin K antagonist combination and 1.30% (95% CrI, 1.02%-1.62%) for the LMWH-vitamin K antagonist combination. Rivaroxaban (HR, 0.55; 95% CrI, 0.35-0.89) and apixaban (HR, 0.31; 95% CrI, 0.15-0.62) were associated with a lower risk of bleeding than was the LMWH-vitamin K antagonist combination, with a lower proportion of patients experiencing a major bleeding event during 3 months of anticoagulation: 0.49% (95% CrI, 0.29%-0.85%) for rivaroxaban, 0.28% (95% CrI, 0.14%-0.50%) for apixaban, and 0.89% (95% CrI, 0.66%-1.16%) for the LMWH-vitamin K antagonist combination.
CONCLUSIONS AND RELEVANCE
Using meta-analytic pooling, there were no statistically significant differences for efficacy and safety associated with most treatment strategies used to treat acute venous thromboembolism compared with the LMWH-vitamin K antagonist combination. However, findings suggest that the UFH-vitamin K antagonist combination is associated with the least effective strategy and that rivaroxaban and apixaban may be associated with the lowest risk for bleeding.
Topics: Acute Disease; Anticoagulants; Hemorrhage; Humans; Risk; Venous Thromboembolism
PubMed: 25226478
DOI: 10.1001/jama.2014.10538 -
Current Problems in Cardiology Jun 2023Transcatheter Aortic Valve Replacement (TAVR) has been established as the treatment of choice for symptomatic aortic stenosis, while it is expanding in all risk-related... (Meta-Analysis)
Meta-Analysis Review
Transcatheter Aortic Valve Replacement (TAVR) has been established as the treatment of choice for symptomatic aortic stenosis, while it is expanding in all risk-related group categories of patients, gaining gradually ground over the surgical approach. However, complications and adverse events are yet to be effectively limited and diminished with thrombotic and hemorrhagic events being rooted as a crucial topic of discussion. Favorable anticoagulation pharmacotherapy options are constantly being revised and tested, whilst guidelines are being modified to meet current clinical evidence. This review aims to systematically assess already existing guidelines on anticoagulation in post-TAVI patients and examine novel regimens for the specific use, like apixaban, rivaroxaban, and other anticoagulants, essentially constructing a holistic point of view on future progress on this matter. The added complexity brought by coagulation-affecting comorbidities such as atrial fibrillation, coronary artery disease, and more contributes to the direct association of the topic to the quality of healthcare as a public service. The literature was systematically searched to examine the effectiveness and safety of various anticoagulation treatments and cross-evaluate them based on the according category of patients that were assigned to. Clinical trials, observational studies and systematic reviews were included and, eventually, conclusive remarks and future considerations were developed and presented. In the category of patients without prior indication to anticoagulation, SAPT was proven safer and still effective, when antiplatelet therapies were compared, while a comparison of antiplatelet versus anticoagulation strategies noted the first one, with limited data, as the optimal one. Lastly, direct oral anticoagulants were shown to be safe substitutes for vitamin K antagonists for patients with prior indication to anticoagulation.
Topics: Humans; Thrombosis; Anticoagulants; Hemorrhage; Transcatheter Aortic Valve Replacement; Rivaroxaban; Treatment Outcome; Platelet Aggregation Inhibitors
PubMed: 36724817
DOI: 10.1016/j.cpcardiol.2023.101632 -
Journal of Thrombosis and Thrombolysis Mar 2024In patients with atrial fibrillation (AF) and normal or slightly impaired renal function, the use of direct oral anticoagulants (DOACs) is preferable to vitamin K... (Meta-Analysis)
Meta-Analysis
Direct oral anticoagulants versus vitamin K antagonists in patients with atrial fibrillation and stage 5 chronic kidney disease under dialysis: A systematic review and meta-analysis of randomized controlled trials.
BACKGROUND
In patients with atrial fibrillation (AF) and normal or slightly impaired renal function, the use of direct oral anticoagulants (DOACs) is preferable to vitamin K antagonists (VKAs). However, in patients undergoing hemodialysis, the efficacy, and safety of DOACs compared with VKAs are still unknown.
PURPOSE
To review current evidence about the safety and efficacy of DOACs compared to VKAs, in patients with AF and chronic kidney disease under hemodialysis.
METHODS
We systematically searched PubMed, Scopus, and Cochrane databases for RCTs comparing DOACs with VKAs for anticoagulation in patients with AF on dialysis therapy. Outcomes of interest were: (1) stroke; (2) major bleeding; (3) cardiovascular mortality; and (4) all-cause mortality. Statistical analysis was performed using RevMan 5.1.7 and heterogeneity was assessed by I statistics.
RESULTS
Three randomized controlled trials were included, comprising a total of 383 patients. Of these, 218 received DOACs (130 received apixaban; 88 received rivaroxaban), and 165 were treated with VKAs (116 received warfarin; 49 received phenprocoumon). The incidence of stroke was significantly lower in patients treated with DOACs (4.7%) compared with those using VKAs (9.5%) (RR 0.42; 95% CI 0.18-0.97; p = 0.04; I = 0%). However, the difference was not statistically significant in the case of ischemic stroke specifically (RR 0.42; 95% CI 0.17-1.04; p = 0.06; I = 0%). As for the major bleeding outcome, the DOAC group (11%) had fewer events than the VKA group (13.9%) but without statistical significance (RR 0.75; 95% CI 0.45-1.28; p = 0.29; I = 0%). There was no significant difference between groups regarding cardiovascular mortality (RR 1.23; 95% CI 0.66-2.29; p = 0.52; I = 13%) and all-cause mortality (RR 0.98; 95% CI 0.77-1.24; p = 0.84; I = 16%).
CONCLUSION
This meta-analysis suggests that in patients with AF on dialysis, the use of DOACs was associated with a significant reduction in stroke, and a numerical trend of less incidence of major bleeding compared with VKAs, but in this case with no statistical significance. Results may be limited by a small sample size or insufficient statistical power.
Topics: Humans; Atrial Fibrillation; Renal Dialysis; Randomized Controlled Trials as Topic; Anticoagulants; Hemorrhage; Stroke; Kidney Failure, Chronic; Fibrinolytic Agents; Vitamin K; Administration, Oral
PubMed: 38281231
DOI: 10.1007/s11239-023-02945-0 -
Thrombosis Research Dec 2020Post-thrombotic syndrome (PTS) is a burdensome long-term complication of deep vein thrombosis (DVT). Recent studies have suggested that rivaroxaban may reduce PTS events... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Post-thrombotic syndrome (PTS) is a burdensome long-term complication of deep vein thrombosis (DVT). Recent studies have suggested that rivaroxaban may reduce PTS events compared to vitamin-K antagonists (VKAs). We, therefore, systematically reviewed available literature that compared rivaroxaban versus VKAs on the risk of PTS.
MATERIALS AND METHODS
We conducted a systematic review and meta-analysis using PubMed, EMBASE and Cochrane Library for all related studies from inception until March 2020. Two reviewers independently screened studies, extracted data, and appraised the quality of included studies. The primary outcome was overall risk of PTS. The secondary outcomes were risks of each PTS category (mild, moderate, severe) and venous ulcer.
RESULTS
Seven comparative studies, comprising 2364 participants, qualified for this meta-analysis. The use of rivaroxaban for DVT treatment was associated with a lower risk of PTS compared with conventional VKAs [pooled unadjusted odds ratio (OR): 0.53, 95%CI: 0.43-0.65, P < 0.00001]. This effect was maintained after adjustment of potential confounders (pooled adjusted OR: 0.44, 95%CI: 0.35-0.56, P < 0.00001). Furthermore, rivaroxaban therapy was found to be associated with reduced risk of mild PTS (OR: 0.64, 95%CI: 0.50-0.82, P = 0.0005), moderate PTS (OR: 0.64, 95%CI: 0.45-0.91, P = 0.01), and severe PTS (OR: 0.52, 95%CI: 0.33-0.82, P = 0.005). There was also a similar trend towards reduced risk for venous ulcer, albeit not statistically significant (OR: 0.41, 95%CI: 0.15-1.08, P = 0.07).
CONCLUSION
In comparison to VKAs, the use of rivaroxaban for DVT treatment has the potential to reduce PTS events. However, well-designed studies with larger sample sizes are needed to corroborate these findings.
Topics: Anticoagulants; Fibrinolytic Agents; Humans; Postthrombotic Syndrome; Rivaroxaban; Vitamins
PubMed: 32977134
DOI: 10.1016/j.thromres.2020.09.014 -
Journal of Clinical GastroenterologySince the introduction of Direct Oral Anticoagulants (DOACs), "real-world" studies have investigated their safety profile on gastrointestinal hemorrhage (GIH) when used...
Safety of Direct Oral Anticoagulants for Gastrointestinal Hemorrhage in Patients With Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-analysis of Real-world Studies.
GOALS AND BACKGROUND
Since the introduction of Direct Oral Anticoagulants (DOACs), "real-world" studies have investigated their safety profile on gastrointestinal hemorrhage (GIH) when used by patients with Non-Valvular Atrial Fibrillation. We performed a systematic review and meta-analysis to compile and summarize this data after Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.
STUDY
Medline and Embase were systematically searched until April 2021. Observational studies that met predefined inclusion criteria were included and hazard ratios (HRs) with 95% CI were extracted. Subgroup analyses based on DOAC doses, history of chronic kidney disease, stroke, prior exposure to VKA (vitamin K antagonist), age, gender, geographic location of population samples, as well as Leave-One-Out and Low/Moderate Risk of Bias sensitivity analyses were performed. A random effects model was used.
RESULTS
A total of 46 studies were included. Apixaban was associated with a reduced risk of GIH compared with Dabigatran (HR: 0.67, 95% CI, 0.56 to 0.81, I2 : 53.28%), Rivaroxaban (HR: 0.56, 95% CI, 0.44 to 0.70, I2 : 79.17%), and VKA (HR: 0.68, 95% CI, 0.60 to 0.78, I2 : 71.93%). Rivaroxaban was associated with increased GIH risk compared with Dabigatran (HR: 1.19, 95% CI, 1.02 to 1.40, I2 : 72.96%) and VKA (HR: 1.16, 95% CI, 1.05 to 1.27, I2 : 81.95%). Dabigatran was associated with similar GIH risk compared with VKA (HR: 1.11, 95% CI, 0.98 to 1.26, I2 : 87.28%).
CONCLUSIONS
Our study shows that Apixaban was associated with a reduction in GIH risk compared with Dabigatran, Rivaroxaban and VKA, whereas Rivaroxaban was associated with an increase in GIH risk compared with both Dabigatran and VKA.
PubMed: 36730651
DOI: 10.1097/MCG.0000000000001796 -
European Journal of Clinical... Oct 2021To explore the efficacy and safety of rivaroxaban in patients with coronary artery disease (CAD), heart failure (HF) and sinus rhythm (SR). (Meta-Analysis)
Meta-Analysis
PURPOSE
To explore the efficacy and safety of rivaroxaban in patients with coronary artery disease (CAD), heart failure (HF) and sinus rhythm (SR).
METHODS
Comprehensive literature searches were conducted using the PubMed, Cochrane Library, Embase, CNKI and Wanfang databases from inception to February 2021. Randomized controlled trials (RCTs) focusing on the efficacy and safety of new oral anticoagulant (NOAC) therapy in CAD and HF patients in SR were eligible. Statistical analyses were performed using R Programming Language.
RESULTS
Three RCTs included 10,658 adult patients treated with antiplatelet drugs with or without rivaroxaban were ultimately analysed. The average follow-up period was 20.4-24 months. Rivaroxaban had a favourable point estimate in myocardial infarction (MI) and stroke (MI rivaroxaban group (3.83%, 203/5306) vs. APT group (4.52%, 214/4731), RR = 0.78, 95% CI 0.65-0.94, P < 0.01, I = 0%), (stroke: rivaroxaban group (1.60%, 85/5306) vs. APT group (2.52%, 119/4731), RR = 0.64, 95% CI 0.49-0.85, P < 0.01, I = 12%) compared with the placebo. Rivaroxaban was comparable to the placebo for all-cause death and major bleeding (all-cause death: rivaroxaban group (12.27%, 688/5606) vs. APT group (14.59%, 737/5052), RR = 0.73, 95% CI 0.49-1.06, P > 0.05, I = 87%), (major bleeding: rivaroxaban group (1.52%, 85/5586) vs. APT group (1.37%, 69/5043), RR = 1.18, 95% CI 0.86-1.62, P > 0.05, I = 0%).
CONCLUSIONS
In SR patients with CAD and HF, the rates of MI and stroke associated with rivaroxaban combined with APT were lower than those associated with APT alone, and the two treatments had similar rates of all-cause death and major bleeding.
Topics: Anticoagulants; Coronary Artery Disease; Heart Failure; Hemorrhage; Humans; Myocardial Infarction; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke
PubMed: 34345970
DOI: 10.1007/s00228-021-03195-w -
Cardiovascular Therapeutics 2021The guidelines on antithrombotic treatment in patients with symptomatic peripheral artery disease (PAD) undergoing peripheral revascularization of the lower extremities... (Meta-Analysis)
Meta-Analysis Review
Efficacy and Safety of Rivaroxaban Compared with Other Therapies Used in Patients with Peripheral Artery Disease Undergoing Peripheral Revascularization: A Systematic Literature Review and Network Meta-Analysis.
BACKGROUND
The guidelines on antithrombotic treatment in patients with symptomatic peripheral artery disease (PAD) undergoing peripheral revascularization of the lower extremities were developed based on heterogeneous trials, assessing various dose regimens and recruiting patients who were subjected to different revascularization procedures.
OBJECTIVE
To compare efficacy and safety of treatments used in patients with PAD undergoing peripheral revascularization accounting for between-trial heterogeneity and large dispersion of the quality of evidence.
METHODS
A systematic literature review of randomised controlled trials (RCTs) recruiting adult patients with PAD receiving antithrombotics was conducted until January 2020. Hazard ratios (HR) were pooled using Bayesian network meta-analysis. The estimated between-treatment effects were presented as HR together with 95% credible intervals. The base case analysis included studies recruiting patients following recent peripheral revascularization, who received treatment regimens administered within the recommended therapeutic window, while a sensitivity scenario included all identified trials.
RESULTS
Thirteen RCTs were identified (8 RCTs enrolled patients following peripheral revascularization and 5 RCTs regardless of the previous revascularization). Five trials, recruiting an overall of 8349 patients, were considered for the base case analysis. Of those, 6564 patients were recruited in the VOYAGER PAD trial comparing rivaroxaban plus aspirin (RIV plus ASA) versus ASA. RIV plus ASA was associated with a lower risk of repeated peripheral revascularization versus ASA monotherapy (HR = 0.88 [0.79, 0.99]), however having a trend towards an increased rate of major bleeding (HR = 1.43 [0.98, 2.11]). There was no evidence for differences between RIV plus ASA and dual antiplatelet therapy and vitamin K antagonists plus ASA. Similar results were observed in sensitivity analyses.
CONCLUSIONS
RIV plus ASA is associated with reduced risk of revascularization compared with ASA monotherapy, but the evidence for other comparators, in particular antiplatelet regimens, was insufficient to guide treatment decisions and highlights the challenge in establishing the magnitude of comparative efficacy using existing RCTs.
Topics: Adult; Aspirin; Humans; Network Meta-Analysis; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Rivaroxaban
PubMed: 34497668
DOI: 10.1155/2021/8561350 -
Annals of Medicine and Surgery (2012) Apr 2024Cerebral venous thromboembolism (CVT) poses a significant risk of venous infarction and haemorrhage, which can lead to neurological deficits and, in severe cases, even... (Review)
Review
BACKGROUND
Cerebral venous thromboembolism (CVT) poses a significant risk of venous infarction and haemorrhage, which can lead to neurological deficits and, in severe cases, even death. The optimal treatment regimen for patients with CVT remains unclear.
METHODS
MEDLINE, Embase, Google Scholar, Web of Science (WoS), and Cochrane Central databases were searched for randomized controlled trials (RCTs) and observational studies assessing the efficacy and safety of rivaroxaban in patients with CVT. All-site venous thromboembolism (VTE), risk of clinically relevant non-major bleeding, incidence of partial recanalization, complete recanalization and major haemorrhage were among outcomes of interest. Mantel-Haenszel weighted random-effects model was used to calculate relative risks (RRs) with 95% CIs.
RESULTS
The analysis included 1 RCT and 3 observational studies containing 211 patients. Compared to vitamin K antagonists (VKAs), rivaroxaban did not significantly decrease the all-site VTE [RR 0.31 (95% CI 0.01, 8.43); =0.49, I=0%]. Compared with VKAs, patients on rivaroxaban did not show a significantly reduced risk of recurrent cerebral venous thrombosis. In terms of incidence of partial recanalization, there was no discernible difference between rivaroxaban and VKAs [RR 0.90 (95% CI 0.66, 1.22); =0.49, I=0%]. There was no discernible difference in incidence of complete recanalization [RR 0.98 (95% CI 0.32, 3.03); =0.97, I=28%] and incidence of major haemorrhage [RR 0.19 (95% CI 0.01, 4.54); =0.30].
CONCLUSION
Rivaroxaban was found to have similar efficacy to VKAs. Due to its lower risk of severe bleeding and no need for INR monitoring, rivaroxaban may be a preferable treatment option for CVT.
PubMed: 38576935
DOI: 10.1097/MS9.0000000000001689