Dataset Information

Meta-analysis of Randomized Controlled Trials of Genotype-Guided vs Standard Dosing of Warfarin.

ABSTRACT:

Background

Warfarin is a widely prescribed anticoagulant, and its effect depends on various patient factors including genotypes. Randomized controlled trials (RCTs) comparing genotype-guided dosing (GD) of warfarin with standard dosing have shown mixed efficacy and safety outcomes. We performed a meta-analysis of all published RCTs comparing GD vs standard dosing in adult patients with various indications of warfarin use.

Methods

We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and relevant references for English language RCTs (inception through March 2014). We performed the meta-analysis using a random effects model.

Results

Ten RCTs with a total of 2,505 patients were included in the meta-analysis. GD compared with standard dosing resulted in a similar % time in therapeutic range (TTR) at ≤ 1 month follow-up (39.7% vs 40.2%; mean difference [MD], -0.52 [95% CI, -3.15 to 2.10]; P = .70) and higher % TTR (59.4% vs 53%; MD, 6.35 [95% CI, 1.76-10.95]; P = .007) at > 1 month follow-up, a trend toward lower risk of major bleeding (risk ratio, 0.46 [95% CI, 0.19-0.1.11]; P = .08) at ≤ 1 month follow-up and lower risks of major bleeding (0.34 [95% CI, 0.16-0.74], P = .006) at > 1-month follow-up, and shorter time to maintenance dose (TMD) (24.6 days vs 34.1 days; MD, -9.54 days [95% CI, -18.10 to -0.98]; P = .03) at follow-up but had no effects on international normalized ratio [INR] > 4.0, nonmajor bleeding, thrombotic outcomes, or overall mortality.

Conclusions

In the first month of genotype-guided warfarin therapy, compared with standard dosing, there were no improvements in % TTR, INR > 4.0, major or minor bleeding, thromboembolism, or all-cause mortality. There was a shorter TMD, and, after 1 month, improved % TTR and major bleeding incidence, making this a cost-effective strategy in patients requiring longer anticoagulation therapy.

SUBMITTER: Dahal K

PROVIDER: S-EPMC4556123 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Publications

Meta-analysis of Randomized Controlled Trials of Genotype-Guided vs Standard Dosing of Warfarin.

Dahal Khagendra K Sharma Sharan P SP Fung Erik E Lee Juyong J Moore Jason H JH Unterborn John N JN Williams Scott M SM

Chest 20150901 3

<h4>Background</h4>Warfarin is a widely prescribed anticoagulant, and its effect depends on various patient factors including genotypes. Randomized controlled trials (RCTs) comparing genotype-guided dosing (GD) of warfarin with standard dosing have shown mixed efficacy and safety outcomes. We performed a meta-analysis of all published RCTs comparing GD vs standard dosing in adult patients with various indications of warfarin use.<h4>Methods</h4>We searched MEDLINE, EMBASE, Cochrane Central Regis ...[more]

PMID: 25811981

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Project description:BackgroundRecently, using the patient's genotype to guide warfarin dosing has gained interest; however, whether pharmacogenetics-based dosing (PD) improves clinical outcomes compared to conventional dosing (CD) remains unclear. Thus, we performed a meta-analysis to evaluate these two strategies.MethodsThe PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese VIP and Chinese Wan-fang databases were searched. The Cochrane Collaboration's tool was used to assess the risk of bias in randomized controlled trials (RCTs). The primary outcome was time within the therapeutic range (TTR); the secondary end points were the time to maintenance dose and time to first therapeutic international normalized ratio (INR), an INR greater than 4, adverse events, major bleeding, thromboembolism and death from any cause.ResultsA total of 11 trials involving 2,678 patients were included in our meta-analysis. The results showed that PD did not improve the TTR compared to CD, although PD significantly shortened the time to maintenance dose (MD = -8.80; 95% CI: -11.99 to -5.60; P<0.00001) and the time to first therapeutic INR (MD = -2.80; 95% CI: -3.45 to -2.15; P<0.00001). Additionally, PD significantly reduced the risk of adverse events (RR = 0.86; 95% CI: 0.75 to 0.99; P = 0.03) and major bleeding (RR = 0.36; 95% CI: 0.15 to 0.89, P = 0.03), although it did not reduce the percentage of INR greater than 4, the risk of thromboembolic events and death from any cause. Subgroup analysis showed that PD resulted in a better improvement in the endpoints of TTR and over-anticoagulation at a fixed initial dosage rather than a non-fixed initial dosage.ConclusionsThe use of genotype testing in the management of warfarin anticoagulation was associated with significant improvements in INR-related and clinical outcomes. Thus, genotype-based regimens can be considered a reliable and accurate method to determine warfarin dosing and may be preferred over fixed-dose regimens.Trial registration prosperoDatabase registration: CRD42015024127.

Project description:BackgroundGenotype-guided warfarin dosing has been shown in some randomized trials to improve anticoagulation outcomes in individuals of European ancestry, yet its utility in Asian patients remains unresolved.MethodsAn open-label, non-inferiority, 1:1 randomized trial was conducted at three academic hospitals in South East Asia, involving 322 ethnically diverse patients newly indicated for warfarin (NCT00700895). Clinical follow-up was 90 days. The primary efficacy measure was the number of dose titrations within the first 2 weeks of therapy, with a mean non-inferiority margin of 0.5 over the first 14 days of therapy.ResultsAmong 322 randomized patients, 269 were evaluable for the primary endpoint. Compared with traditional dosing, the genotype-guided group required fewer dose titrations during the first 2 weeks (1.77 vs. 2.93, difference -1.16, 90% CI -1.48 to -0.84, P < 0.001 for both non-inferiority and superiority). The percentage of time within the therapeutic range over 3 months and median time to stable international normalized ratio (INR) did not differ between the genotype-guided and traditional dosing groups. The frequency of dose titrations (incidence rate ratio 0.76, 95% CI 0.67 to 0.86, P = 0.001), but not frequency of INR measurements, was lower at 1, 2, and 3 months in the genotype-guided group. The proportions of patients who experienced minor or major bleeding, recurrent venous thromboembolism, or out-of-range INR did not differ between both arms. For predicting maintenance doses, the pharmacogenetic algorithm achieved an R2 = 42.4% (P < 0.001) and mean percentage error of -7.4%.ConclusionsAmong Asian adults commencing warfarin therapy, a pharmacogenetic algorithm meets criteria for both non-inferiority and superiority in reducing dose titrations compared with a traditional dosing approach, and performs well in prediction of actual maintenance doses. These findings imply that clinicians may consider applying a pharmacogenetic algorithm to personalize initial warfarin dosages in Asian patients.Trial registrationClinicalTrials.gov NCT00700895 . Registered on June 19, 2008.

Project description:Warfarin is a traditional oral anticoagulant for preventing thrombotic events in patients with atrial fibrillation (AF) and venous thromboembolism. Along with the widespread clinical use, the potential association between warfarin use and fracture risk have been addressed gradually. Non-vitamin K antagonist oral anticoagulants (NOACs), targeting thrombin or Xa factor, have been recommended as an optimal alternative due to their favorable property of thromboembolism prophylaxis and reduced bleeding risk. However, evidence of the fracture risk with NOACs use is limited. Therefore, the present study investigated this issue by a meta-analysis. Medline, Embase, Cochrane Library and the ClinicalTrials.gov Website were searched for randomized controlled trials (RCTs) that reported the fracture data of NOACs and warfarin. The primacy outcome was a composite of any fracture. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random- or fixed-effects models according to between-study heterogeneity. Heterogeneity was assessed through I2 test and Q statistic, and the number of patients needed to treat (NNT) was calculated based on fracture incidence. Subgroup analyses were conducted according to individual NOACs, indications, and duration of follow up. Finally, 12 RCTs involving 89,549 patients were included, among which 44,816 (50%) receiving NOACs and 44,733 (50%) receiving warfarin. Overall, 1,139 (1.3%) patients including 515 NOACs users (1.1%) and 624 warfarin users (1.4%) developed fracture. Risk of fracture was significantly lower in NOACs compared to warfarin (RR: 0.82, 95%CI: 0.73-0.93, P = 0.001), with a NNT of 333. No significantly decreased risk was detected according to fracture sites. Subgroup analysis confirmed that the estimate of decreased fracture risk was derived mainly from AF patients receiving long-term anticoagulation treatment. The meta-regression did not detect any potential confounding on fracture risk. No heterogeneity between the studies (I2 = 15.0%) and no publication bias was identified. In conclusion, the use of NOACs was associated with a lower risk of fracture compared to warfarin, but with a relatively low absolute risk reduction. Therefore, screening for the fracture risk should be considered before initiating anticoagulation treatment. For patients who are at high risk of fracture or expected long-term treatment of anticoagulation, NOACs may represent a preferable alternative to warfarin.

Project description:BackgroundWhether guided antiplatelet therapy in patients with acute coronary syndrome (ACS) is effective in improving net clinical benefits compared with conventional antiplatelet therapy remains controversial. Therefore, we assessed the safety and efficacy of guided antiplatelet therapy in patients with ACS and undergoing percutaneous coronary intervention.MethodWe searched PubMed, EMBASE, and Cochrane Library databases to select the relevant randomized controlled trials comparing the guided and conventional antiplatelet therapy in patients with ACS. The primary and safety outcomes are major adverse cardiovascular events (MACE) and major bleeding, respectively. The efficacy outcomes included myocardial infarction, stent thrombosis, all-cause death, and cardiovascular death. We selected the relative risk (RR) and 95% confidence intervals (CIs) as effect size and calculated it using the Review Manager software. In addition, we evaluated the final results by trial sequential analysis (registered by PROSPERO, CRD 42020210912).ResultsWe selected seven randomized controlled trials and included 8,451 patients in this meta-analysis. Guided antiplatelet therapy can significantly reduce the risk of MACE (RR 0.64, 95% CI 0.54-0.76, P < 0.00001), myocardial infarction (RR 0.62, 95% CI 0.49-0.79, P = 0.0001), all-cause death (RR 0.61, 95% CI 0.44-0.85, P = 0.003), and cardiovascular death (RR 0.66, 0.49-0.90, P = 0.009). In addition, there is no significant difference between the two groups in stent thrombosis (RR 0.67, 95% CI 0.44-1.03, P = 0.07) and major bleeding (RR 0.86, 95% CI 0.65-1.13, P = 0.27). The subgroup analysis showed that the guided group based on genotype tests could bring benefits in MACE and myocardial infarction.ConclusionsThe guided antiplatelet therapy is not only associated with a comparable risk of bleeding but also with a lower risk of MACE, myocardial infarction, all-cause death, cardiovascular death, and stent thrombosis than the conventional strategy in patients with ACS.

Project description:Background and study aims Hemospray (TC-325) is a mineral powder with adsorptive properties designed for use in various gastrointestinal bleeding (GIB) scenarios. We conducted a systematic review & meta-analysis of randomized controlled trials (RCTs) comparing TC-325 to standard endoscopic therapy (SET) for non-variceal GIB (NVGIB). Methods Multiple databases were searched through October 2022. Meta-analysis was performed using a random-effects model to determine pooled relative risk (RR) and proportions with 95 % confidence intervals (CI) for primary hemostasis, hemostasis failure, 30-day rebleeding, length of stay (LOS), and need for rescue interventions. Heterogeneity was assessed using I 2 %. Results Five RCTs with 362 patients (TC-325 178, SET 184) - 123 females and 239 males with a mean age 65 ± 16 years). The most common etiologies were peptic ulcer disease (48 %), malignancies (35 %), and others (17 %). Bleeding was characterized as Forrest IA (7 %), IB (73 %), IIA (3 %), and IIB (1 %). SET included epinephrine injection, electrocautery, hemoclips, or a combination. No statistical difference in primary hemostasis between TC-325 compared to SET, RR 1.09 (CI 0.95-1.25; I 2 43), P = 0.2, including patients with oozing/spurting hemorrhage, RR 1.13 (CI 0.98-1.3; I 2 35), P = 0.08. Failure to achieve hemostasis was higher in SET compared to TC-325, RR 0.30 (CI 0.12-0.77, I 2 0), P = 0.01, including patients with oozing/spurting hemorrhage, RR 0.24 (CI 0.09 - 0.63, I 2 0), P = 0.004. We found no difference between the two interventions in terms of rebleeding, RR 1.13 (CI 0.62-2.07, I 2 26), P = 0.8 and LOS, standardized mean difference (SMD) 0.27 (CI, -0.20-0.74; I 2 62), P = 0.3. Finally, pooled rate of rescue interventions (angiography) was statistically higher in SET compared to TC-325, RR 0.68 (CI 0.5-0.94; I 2 0), P = 0.02. Conclusions Our analysis shows that for acute NV GIB, including oozing/spurting hemorrhage, TC-325 does not result in higher rates of primary hemostasis compared to SET. However, lower rates of failures were seen with TC-325 than SET. In addition, there was no difference in the two modalities when comparing rates of rebleeding and LOS.

Project description:BackgroundWarfarin is the only approved anticoagulant for antithrombotic treatment in patients with mechanical prosthetic heart valves (MPHV). However, dosing warfarin is challenging due to its narrow therapeutic window and highly variable clinical outcomes. Both low and high doses of warfarin can lead to thrombotic and bleeding events, respectively, with these complications being more severe in individuals with sensitive genetic polymorphisms. Incorporating genetic testing could enhance the accuracy of warfarin dosing and minimize its adverse events.ObjectivesThis study aims to evaluate the utilities and cost-effectiveness of pharmacogenomics-guided versus standard dosing of warfarin in patients with MPHV in Iran.MethodsIn this economic evaluation study, a cost-effectiveness analysis was conducted to compare pharmacogenomics-guided versus standard warfarin dosing. Data related to quality of life (QoL) were collected through a cross-sectional study involving 105 randomly selected MPHV patients using the EuroQol-5D (EQ-5D) Questionnaire. Costs were calculated with input from clinical experts and a review of relevant guidelines. Additional clinical data were extracted from published literature. The pharmacoeconomic threshold set for medical interventions within Iran's healthcare system was $1,500. A decision tree model was designed from the perspective of Iran's healthcare system with a one-year study horizon. Sensitivity analyses were also performed to assess the uncertainty of input parameters.ResultsThe utility scores derived from the questionnaire for standard and pharmacogenomics-guided warfarin treatments were 0.68 and 0.76, respectively. Genotype-guided dosing of warfarin was more costly compared to the standard dosing ($246 vs $69), and the calculated incremental cost-effectiveness ratio (ICER) was $2474 per quality-adjusted life year (QALY) gained. One-way sensitivity analyses showed that our model is sensitive to the percentage of time in the therapeutic range (PTTR), the cost of genetic tests, and the utility of both pharmacogenomics-guided and standard dosing arms. However, the probabilistic sensitivity analysis demonstrates the robustness of our model.ConclusionsWarfarin dosing with pharmacogenomics testing is currently not cost-effective. However, if the cost of genotyping tests decreases to $118, the ICER would become cost-effective.

Dataset Information

Meta-analysis of Randomized Controlled Trials of Genotype-Guided vs Standard Dosing of Warfarin.

Background

Methods

Results

Conclusions

Publications

Meta-analysis of Randomized Controlled Trials of Genotype-Guided vs Standard Dosing of Warfarin.

Similar Datasets

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