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Systematic review with meta-analysis: impact of baseline resistance-associated substitutions on the efficacy of glecaprevir/pibrentasvir among chronic hepatitis C patients.
Singh, AD, Maitra, S, Singh, N, Tyagi, P, Ashraf, A, Kumar, R, Shalimar,
Alimentary pharmacology & therapeutics. 2020;(5):490-504
Abstract
BACKGROUND The effect of baseline resistance-associated substitutions (RAS) on the sustained virologic response at 12 weeks (SVR12) among chronic hepatitis C (CHC) patients receiving the second generation, pan-genotypic glecaprevir/pibrentasvir (G/P) regimen is unclear. AIM: To assess the effect of RAS on the SVR12 in CHC patients treated with G/P regimen. METHODS The EMBASE, MEDLINE and Cochrane central register of controlled trials databases were searched for relevant studies published before 1 March 2019. The principal outcome was to compare the SVR12 in CHC patients with and without baseline RAS, particularly in genotype-1, genotype-3 and direct-acting anti-virals (DAAs) failure patients. The outcomes were pooled using a random-effects model and odds ratio (OR) was calculated. The risk of bias was assessed using the Cochrane risk of bias tools for randomised and nonrandomised interventional studies. RESULTS After initially identifying 410 studies, 3302 patients from 17 studies were included. Among 50 cases of virologic failures, 48% had genotype-3 infection, 44% genotype-1 infection and 36% DAA-failure patients. Baseline RAS were present in 44(88%) patients. The most common NS5a and NS3 mutations were Y93H and A166S respectively. The odds of SVR12 were significantly reduced in patients with any baseline RAS (NS3 and/or NS5a) (OR 0.32, 95%C I[0.15, 0.65], I2 = 0%) and NS5a substitutions (OR 0.36, 95%CI [0.18,0.73]). The impact of RAS on SVR12 was significant among genotype-3 patients, but not among genotype-1 or DAA-failure cases. The presence of Y93H and A30K mutations significantly impacted SVR12 rates in genotype-3 patients. CONCLUSION Baseline NS3 or NS5a RAS, especially the NS5a substitutions-A30K, Y93H, decrease the odds of achieving SVR12 in genotype-3 CHC patients.
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Comparative coronary risks of apixaban, rivaroxaban and dabigatran: a meta-analysis and adjusted indirect comparison.
Loke, YK, Pradhan, S, Yeong, JK, Kwok, CS
British journal of clinical pharmacology. 2014;(4):707-17
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Abstract
AIMS: There are concerns regarding increased risk of acute coronary syndrome with dabigatran. We aimed to assess whether alternative treatment options such as rivaroxaban or apixaban carry a similar risk as compared with dabigatran. METHODS We searched MEDLINE and EMBASE for randomized controlled trials of apixaban, dabigatran or rivaroxaban against control (placebo, heparin or vitamin K antagonist). We pooled odds ratios (OR) for adverse coronary events (acute coronary syndrome or myocardial infarction) using fixed effect meta-analysis and assessed heterogeneity with I(2) . We conducted adjusted indirect comparisons to compare risk of adverse coronary events with apixaban or rivaroxaban vs. dabigatran. RESULTS Twenty-seven randomized controlled trials met the inclusion criteria. Dabigatran was associated with a significantly increased risk of adverse coronary events in pooled analysis of nine trials (OR 1.45, 95% CI 1.14, 1.86). There was no signal for coronary risk with apixaban from nine trials (pooled OR 0.89, 95% CI 0.78, 1.03) or rivaroxaban from nine trials (pooled OR 0.81, 95% CI 0.72, 0.93). Overall, adjusted indirect comparison suggested that both apixaban (OR 0.61, 95% CI 0.44, 0.85) and rivaroxaban (OR 0.54; 95% CI 0.39, 0.76) were associated with lower coronary risk than dabigatran. Restricting the indirect comparison to a vitamin K antagonist as a common control, yielded similar findings, OR 0.57 (95% CI 0.39, 0.85) for apixaban vs. dabigatran and 0.53 (95% CI 0.37, 0.77) for rivaroxaban vs. dabigatran. CONCLUSIONS There are significant differences in the comparative safety of apixaban, rivaroxaban and dabigatran with regards to acute coronary adverse events.
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Meta-analysis of efficacy and safety of rivaroxaban compared with warfarin or dabigatran in patients undergoing catheter ablation for atrial fibrillation.
Aryal, MR, Ukaigwe, A, Pandit, A, Karmacharya, P, Pradhan, R, Mainali, NR, Pathak, R, Jalota, L, Bhandari, Y, Donato, A
The American journal of cardiology. 2014;(4):577-82
Abstract
Several studies have been conducted to study the efficacy and safety of rivaroxaban in the atrial fibrillation periprocedural ablation period with similar rates of thromboembolism and major bleeding risks compared with warfarin or dabigatran. We sought to systematically review this evidence using pooled data from multiple studies. Studies comparing rivaroxaban with warfarin or dabigatran in patients undergoing catheter ablation for atrial fibrillation were identified through electronic literature searches of MEDLINE, EMBASE, clinicaltrials.gov, and the Cochrane library up to March 2014. Study-specific risk ratios (RRs) were calculated and combined using a random-effects model meta-analysis. In an analysis involving 3,575 patients, thromboembolism (composite of stroke, transient ischemic attack, and systemic and pulmonary emboli) occurred in 3 of 789 patients (0.4%) in the rivaroxaban group and 10 of 2,786 patients (0.4%) in the warfarin group (RR 0.71, 95% CI 0.26 to 1.96, I(2) = 0%, p = 0.51). Major hemorrhage occurred in 9 of 749 patients (1.2%) in the rivaroxaban group and 22 of 975 patients (2.3%) in the warfarin group (RR 0.49, 95% CI 0.24 to 1.02, I(2) = 0%, p = 0.06). Furthermore, direct efficacy and safety comparisons between rivaroxaban and dabigatran showed nonsignificant differences in rates of thromboembolism (0.5% vs 0.4%, respectively, RR 1.12, 95% CI 0.25 to 4.99, I(2) = 0%, p = 0.88) and major bleeding (1.0% vs 1.6%, respectively, RR = 0.71, 95% CI 0.16 to 3.15, I(2) = 22%, p = 0.66). In conclusion, our study suggests that patients treated with rivaroxaban during periprocedural catheter ablation have similar rates of thromboembolic events and major hemorrhage. Similar results were seen in direct comparisons between dabigatran and rivaroxaban.
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Risk of major bleeding and the standard doses of dabigatran.
Antoniazzi, S, Berdaï, D, Conti, V, Clementi, E, Salvo, F
European journal of internal medicine. 2014;(6):e73-5
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Safety and efficacy of dabigatran versus warfarin in patients undergoing catheter ablation of atrial fibrillation: a systematic review and meta-analysis.
Providência, R, Albenque, JP, Combes, S, Bouzeman, A, Casteigt, B, Combes, N, Narayanan, K, Marijon, E, Boveda, S
Heart (British Cardiac Society). 2014;(4):324-35
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BACKGROUND Dabigatran etexilate, a new thrombin inhibitor, has been shown to be comparable to warfarin in patients with atrial fibrillation (AF). However, there is a limited body of evidence on the efficacy and safety of using dabigatran among patients undergoing AF catheter ablation. OBJECTIVE A random effects meta-analysis was performed of controlled trials comparing dabigatran and warfarin in paroxysmal/persistent AF patients undergoing catheter ablation. METHODS Data sources included Medline, Embase, and Cochrane (from inception to April 2013). Three independent reviewers selected studies comparing warfarin to dabigatran. Descriptive and quantitative information was extracted from each selected study, regarding periprocedural all cause mortality, thromboembolic events and major bleeding, as well as modalities of periprocedural anticoagulation bridging. RESULTS After a detailed screening of 228 search results, 14 studies were identified enrolling a total of 4782 patients (1823 treated with dabigatran and 2959 with warfarin). No deaths were reported. No significant differences were found between patients treated with dabigatran and warfarin as regards thromboembolic events (0.55% dabigatran vs 0.17% warfarin; risk ratios (RR)=1.78, 95% CI 0.66 to 4.80; p=0.26) and major bleeding (1.48% dabigatran vs 1.35% warfarin; RR=1.07, 95% CI 0.51 to 2.26; p=0.86). No difference was found between the 110 mg twice daily and 150 mg twice daily dabigatran dosages concerning major bleeding (0% vs 1.62%, respectively; RR=0.19, 95% CI 0.01 to 3.18; p=0.25) and thromboembolism (0% vs 0.40%, respectively; RR=0.72, 95% CI 0.04 to 12.98; p=0.82). CONCLUSIONS In the specific setting of AF catheter ablation, this first pooled analysis suggests that patients treated with dabigatran have a similar incidence of thromboembolic events and major bleeding compared to warfarin, with low event rates overall.
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A comparison of results of the US food and drug administration's mini-sentinel program with randomized clinical trials: the case of gastrointestinal tract bleeding with dabigatran.
Sipahi, I, Celik, S, Tozun, N
JAMA internal medicine. 2014;(1):150-1
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Dabigatran for periprocedural anticoagulation following radiofrequency ablation for atrial fibrillation: a meta-analysis of observational studies.
Steinberg, BA, Hasselblad, V, Atwater, BD, Bahnson, TD, Washam, JB, Alexander, JH, Daubert, JP, Piccini, JP
Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing. 2013;(3):213-21
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PURPOSE Dabigatran is approved for prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF). The safety and effectiveness of periprocedural dabigatran in ablation for AF are unknown. METHODS We performed a meta-analysis of all studies comparing periprocedural dabigatran with warfarin for anticoagulation in AF ablation. Studies of >100 patients with post-procedure follow-up were included. Outcomes were compared by calculating maximum likelihood estimates with confidence intervals. The co-primary endpoints were neurological events and major bleeding. RESULTS Ten cohort studies were included, including a total of 1,501 patients receiving dabigatran and 2,356 receiving warfarin. The mean age was 59-64 years and inclusion of women varied (10-33 %). Intra-procedural unfractionated heparin and irrigated ablation catheters were used routinely. Adverse events were low overall; however, the dabigatran group demonstrated a numerical excess of neurological events (10/1,501 [0.7 %] versus 4/2,356 [0.2 %]), but equivalent major bleeding outcomes (24/1,501 [1.6 %] versus 40/2,356 [1.7 %]). In the meta-analysis, there was a nonsignificant trend towards higher rates of the composite primary endpoints (any neurological event or major bleeding) in the dabigatran group. Dabigatran demonstrated a significantly higher rate of neurological events (estimated absolute risk difference 0.0047, 95 % confidence interval 0.0007 to 0.0099). CONCLUSIONS Compared with warfarin, dabigatran may be associated with a higher frequency of periprocedural neurological events following radiofrequency ablation of AF. Randomized clinical trials are needed to definitively assess the safety and efficacy of novel oral anticoagulant use for periprocedural anticoagulation for ablation of AF.
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Safety and efficacy of dabigatran compared with warfarin for patients undergoing radiofrequency catheter ablation of atrial fibrillation: a meta-analysis.
Shurrab, M, Morillo, CA, Schulman, S, Kansal, N, Danon, A, Newman, D, Lashevsky, I, Healey, JS, Crystal, E
The Canadian journal of cardiology. 2013;(10):1203-10
Abstract
BACKGROUND The safety and efficacy of dabigatran in the periprocedural period for patients undergoing atrial fibrillation ablation is not well established. We conducted a meta-analysis of the periprocedural use of dabigatran vs warfarin (with or without heparin bridging). METHODS A literature search was performed using multiple databases. Outcomes were (1) major bleeding; (2) minor bleeding; and (3) thromboembolic events. Odds ratios (ORs) were reported for dichotomous variables. RESULTS Eleven controlled studies (9 cohorts, 1 randomized controlled trial and 1 case-control study; 3841 patients) were identified. Dabigatran was used in 1463 patients, uninterrupted in 223 and held up to 36 hours in the remainder. No significant differences were noted in major bleeding rates between dabigatran and warfarin groups (1.9% vs. 1.6%; OR, 1.04 [95% confidence interval (CI), 0.51-2.13]; P = 0.92). Cardiac tamponade was observed in 1.4% in dabigatran vs 1.1% in warfarin groups (OR, 1.1; 95% CI, 0.55-2.11; P = 0.82). Similar rates for dabigatran vs. warfarin were reported for minor bleeding (3.8% vs. 4.5%; OR, 0.85; 95% CI, 0.58-1.25; P = 0.40), hematoma (2% vs. 2.7%; OR, 0.67; 95% CI, 0.41-1.08; P = 0.1), and thromboembolic events (0.6% vs. 0.1%; OR, 2.51; 95% CI, 0.78-8.11; P = 0.12). CONCLUSIONS This meta-analysis suggests that dabigatran and warfarin have similar safety and efficacy overall for periprocedural anticoagulation in patients undergoing radiofrequency atrial fibrillation ablation. Signals were seen favouring dabigatran (for hematomas) and warfarin (for thromboembolic events), but neither was statistically significant because of low event rates. More high-quality data are required to definitively compare the 2 strategies.
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Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitors.
Artang, R, Rome, E, Nielsen, JD, Vidaillet, HJ
The American journal of cardiology. 2013;(12):1973-9
Abstract
Dabigatran has been associated with greater risk of myocardial infarction (MI) than warfarin. It is unknown whether the increased risk is unique to dabigatran, an adverse effect shared by other oral direct thrombin inhibitors (DTIs), or the result of a protective effect of warfarin against MI. To address these questions, we systematically searched MEDLINE and performed a meta-analysis on randomized trials that compared oral DTIs with warfarin for any indication with end point of MIs after randomization. We furthermore performed a secondary meta-analysis on atrial fibrillation stroke prevention trials with alternative anticoagulants compared with warfarin with end point of MIs after randomization. A total of 11 trials (39,357 patients) that compared warfarin to DTIs (dabigatran, ximelagatran, and AZD0837) were identified. In these trials, patients treated with oral DTIs were more likely to experience an MI than their counterparts treated with warfarin (285 of 23,333 vs 133 of 16,024, odds ratio 1.35, 95% confidence interval 1.10 to 1.66, p = 0.005). For secondary analysis, 8 studies (69,615 patients) were identified that compared warfarin with alternative anticoagulant including factor Xa inhibitors, DTIs, aspirin, and clopidogrel. There was no significant advantage in the rate of MIs with the use of warfarin versus comparators (odds ratio 1.06, 95% confidence interval 0.85 to 1.34, p = 0.59). In conclusion, our data suggest that oral DTIs were associated with increased risk of MI. This increased risk appears to be a class effect of these agents, not a specific phenomenon unique to dabigatran or protective effect of warfarin. These findings support the need for enhanced postmarket surveillance of oral DTIs and other novel agents.
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Effects of telmisartan therapy on interleukin-6 and tumor necrosis factor-alpha levels: a meta-analysis of randomized controlled trials.
Takagi, H, Mizuno, Y, Yamamoto, H, Goto, SN, Umemoto, T, ,
Hypertension research : official journal of the Japanese Society of Hypertension. 2013;(4):368-73
Abstract
A recent meta-analysis of randomized head-to-head trials suggests that therapy with telmisartan, an angiotensin II receptor blocker (ARB) and partial agonist of peroxisome proliferator-activated receptor-gamma, may increase adiponectin levels more strongly than other ARB therapies. Therefore, telmisartan would be expected to reduce interleukin-6 (IL-6) or tumor necrosis factor-alpha (TNF-α). To determine whether telmisartan reduces IL-6 or TNF-α, we performed the first meta-analysis of randomized controlled trials of telmisartan therapy. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched through November 2011. Eligible studies were prospective randomized controlled trials of telmisartan vs. unrestricted control therapy reporting IL-6 or TNF-α levels as an outcome. For each study, data regarding percent changes from baseline to final IL-6 or TNF-α levels in both the telmisartan and control groups were used to generate standardized mean differences (SMDs) and 95% confidence intervals (CIs). Nine reports of randomized trials enrolling a total of 645 patients were identified. Pooled analysis of seven and five trials demonstrated a statistically significant reduction in percent changes of IL-6 (fixed-effects SMD, -0.385; 95% CI, -0.581 to -0.189; P<0.001; P for heterogeneity=0.073) and TNF-α levels (random-effects SMD, -0.627; 95% CI, -0.945 to -0.308; P<0.001; P for heterogeneity=0.029) with telmisartan relative to control therapy, respectively. In conclusion, based on a meta-analysis of nine randomized controlled trials, telmisartan therapy is likely effective in reducing IL-6 and TNF-α levels.