Association Between Diabetic Retinopathy and Cognitive Impairment: A Systematic Review and Meta-Analysis

Diabetic retinopathy (DR) is one of the most common microvascular complications associated with diabetes mellitus. However, its correlation with another diabetes-related disorder, cognitive impairment, has not been well studied. This systematic review and meta-analysis aimed to explore the association between DR and cognitive impairment. MEDLINE (PubMed), the Cochrane Library, and EMBASE databases were searched for observational studies that reported an association between DR and cognitive impairment. Data from selected studies were extracted, and a meta-analysis was conducted using fixed-effects modeling. Fifteen observational studies were included in the systematic review, and 10 studies were included in the meta-analysis. The odds ratio of the association between DR and cognitive impairment was 2.24 (95% confidence interval [CI], 1.89–2.66; I2 = 0.8%). The hazard ratio of the association between DR and cognitive impairment was significant in four studies, ranging from 1.09–1.32. Minimal or mild DR was not significantly associated with cognitive impairment (odds ratio [OR], 2.04; 95% CI, 0.87–4.77). However, the association between proliferative DR and cognitive impairment (OR, 3.57; 95% CI, 1.79–7.12; I2 = 16.6%) was not stronger than the association between moderate or worse DR and cognitive impairment (OR, 4.26; 95% CI, 2.01–9.07; I2 = 0.0%). DR is associated with cognitive impairment, and screening for DR will be helpful for the early identification of individuals with cognitive impairment. Further studies are needed to confirm the association between proliferative DR and cognitive impairment.

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Direct and Indirect Therapeutic Effect of Traditional Chinese Medicine as an Add-on for Non-proliferative Diabetic Retinopathy: A Systematic Review and Meta-analysis

10.21203/rs.3.rs-51831/v2 ◽

2020 ◽

Author(s):

Xuedong an ◽

de jin ◽

liyun duan ◽

shenghui zhao ◽

rongrong zhou ◽

...

Keyword(s):

Risk Factors ◽

Systematic Review ◽

Diabetic Retinopathy ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Fixed Effects ◽

Meta Analysis ◽

Random Effect Model ◽

Small Sample ◽

Cochrane Library

Abstract Background：Diabetic retinopathy (DR) is the leading cause of blindness in many countries. The current treatment for non-proliferative DR (NPDR) using Western medicine (WM) alone is insufficient. At present, the combination of NPDR treatment with traditional Chinese medicine (TCM) and WM is universally applied. We aimed to evaluate the effectiveness and safety of TCM as an add-on for NPDR using a systematic review and meta-analysis.Method: Data from randomized controlled trials (RCTs) of TCM for NPDR treatment along with WM before July 6, 2019, were collected from the China National Knowledge Infrastructure, Wanfang Database, China Biomedical Database, Pubmed, Embase, and Cochrane Library. Relevant data were extracted by two reviewers. I2 statistics was adopted to appraise heterogeneity. If I2<50% the fixed-effects model was employed, otherwise a random-effect model was employed. (PROSPERO: CRD42019134947)Result: Eighteen RCTs (1522 patients) were included based on the inclusion and exclusion criteria. The results showed that compared with WM alone, TCM (including Compound Xueshuantong Capsule, Qiming Granule, and others) combined with WM for NPDR could improve the overall effiicacy [n=1686，RR1.24(1.18,1.30), P<0.00001, I2=0%], and reduce the influence of risk factors related to NPDR, such as glycated hemoglobin level [n=360, MD -0.85(-1.28, -0.41), P=0.0001, I2=72%], triglyceride (P<0.00001), and total cholesterol (P=0.0008). Moreover, no serious adverse events were reported.Conclusion: Compared with WM alone, TCM+WM could significantly improve NPDR and also reduce the correlation levels of risk factors, such as hyperglycemia, dyslipidemia. However, the small sample included in the study might lead to a publication bias, and therefore, our results should be treated with caution.

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Vitamin D Deficiency Increases the Risk of Diabetic Retinopathy: A Meta-Analysis of Observational Studies

10.20944/preprints201704.0059.v1 ◽

2017 ◽

Author(s):

Xiang Zhang ◽

Guo-Tao Pan ◽

Zeng-Li Zhang ◽

Shasha Tao

Keyword(s):

Vitamin D ◽

Diabetic Retinopathy ◽

Vitamin D Deficiency ◽

Observational Studies ◽

Meta Analysis ◽

Microvascular Complications ◽

Final Analysis ◽

Cochrane Library ◽

Diabetic Patients ◽

The Cochrane Library

Background: Diabetic retinopathy (DR) is one of the most prominent pathological microvascular complications in diabetes. A series of studies reported that vitamin D deficiency was associated with increased prevalence of retinopathy in diabetic patients but the results were inconsistent. In this study we focused on evaluating the relationship between vitamin D deficiency and DR by conducting a meta-analysis of observational studies. Methods: Systematic computerized searches were performed in PubMed, MEDLINE, and the Cochrane Library for relevant original articles till November 20, 2016. The pooled odds ratios (ORs) with corresponding confidence intervals (CIs) were calculated to assess the associated value of vitamin D deficiency to the risk of DR. 9 studies including 6332 participants were subjected to final analysis. Results: The results indicated that vitamin D deficiency increases the risk of DR (OR = 1.57, 95% CI 1.32-1.87) with a little heterogeneity (I2 = 23%). In addition, the subgroup analysis demonstrated that there were obvious heterogeneities in T2DM (I2 = 47.8%). Sensitivity analysis showed that the results were relatively stable and reliable. Conclusion: our meta-analysis demonstrated that vitamin D deficiency could increase the risk of DR.

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The Efficacy and Safety of Infliximab in Refractory Noninfectious Uveitis: A Meta-Analysis of Observational Studies

Frontiers in Pharmacology ◽

10.3389/fphar.2021.620340 ◽

2021 ◽

Vol 12 ◽

Author(s):

Anji Xiong ◽

Deng Liu ◽

Huini Chen ◽

Guancui Yang ◽

Chen Xiong ◽

...

Keyword(s):

Systematic Review ◽

Visual Acuity ◽

Observational Studies ◽

Fixed Effects ◽

Meta Analysis ◽

Intraocular Inflammation ◽

Cochrane Library ◽

Efficacy And Safety ◽

Serious Adverse Events

Background: Although infliximab has been recommended for the second-line treatment of seronegative spondyloarthropathy- or juvenile idiopathic arthritis-related uveitis, the issue of its systemic efficacy and safety in a broader diversity of refractory noninfectious uveitis is debatable. To assess the short-term and relatively long-term efficacy of infliximab in refractory noninfectious uveitis, we performed a systematic review and meta-analysis of observational studies.Methods: PubMed, Cochrane Library, EMBASE, and Wanfang Med Online were systematically searched from January 2005 to March 2020. Two investigators independently assessed eligibility. Data were independently collected by two investigators. The pooled proportions were estimated with patients for intraocular inflammation control and improvement of visual acuity. Pooled proportions with 95% credible intervals were computed. Study homogeneity was investigated using I2 statistics to quantify the percentage of variation across studies. To pool the results, the Mantel–Haenszel fixed-effects or random-effects models were used.Results: Of 2316 studies identified, 16 unique studies with 509 unique participants were included in the meta-analysis. The pooled proportions of intraocular inflammation control reached 92% (95% CI: 87%–98%; I2: 1%; p=0.42) and 95% (95% CI: 93%–97%; I2: 0%; p=0.91) in groups of ≤6- and ≥12-month follow-up durations. During the relatively long follow-up period, the pooled proportions of maintaining visual acuity stable or increasing at least one line reached 99% (95% CI: 96%–100%; I2: 0%; p=0.54) in the involved eyes. The corticosteroid-sparing effect of infliximab was also well demonstrated, with the proportion of corticosteroid-sparing success reaching 85.5% (112/131). Besides, about serious adverse events, 2.6% (13/500) of patients experienced hypersensitivity reactions, 2.4% (12/500) of patients experienced serious infections, 1.8% (9/500) of patients experienced autoimmune diseases, and 0.6% (3/500) of patients experienced neoplasia.Conclusions: This meta-analysis provided evidence that infliximab might be a promising choice in controlling inflammatory activity, gaining visual acuity, and sparing corticosteroid use with relatively few side effects when applied in treating refractory noninfectious uveitis.Systematic Review Registration: [website], identifier [registration number]

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Direct and indirect therapeutic effect of traditional Chinese medicine as an add-on for non-proliferative diabetic retinopathy: a systematic review and meta-analysis

Chinese Medicine ◽

10.1186/s13020-020-00380-4 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Xuedong An ◽

De Jin ◽

LiYun Duan ◽

Shenghui Zhao ◽

Rongrong Zhou ◽

...

Keyword(s):

Risk Factors ◽

Systematic Review ◽

Diabetic Retinopathy ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Fixed Effects ◽

Meta Analysis ◽

Random Effect Model ◽

Small Sample ◽

Cochrane Library

Abstract Background Diabetic retinopathy (DR) is the leading cause of blindness in many countries. The current treatment for non-proliferative DR (NPDR) using Western medicine (WM) alone is insufficient. At present, the combination of NPDR treatment with traditional Chinese medicine (TCM) and WM is universally applied. We aimed to evaluate the effectiveness and safety of TCM as an add-on for NPDR using a systematic review and meta-analysis. Method Data from randomized controlled trials (RCTs) of TCM for NPDR treatment along with WM before July 6, 2019, were collected from the China National Knowledge Infrastructure, Wanfang Database, China Biomedical Database, Pubmed, Embase, and Cochrane Library. Relevant data were extracted by two reviewers. I2 statistics was adopted to appraise heterogeneity. If I2 < 50% the fixed-effects model was employed, otherwise a random-effect model was employed. (PROSPERO: CRD42019134947) Result Eighteen RCTs (1522 patients) were included based on the inclusion and exclusion criteria. The results showed that compared with WM alone, TCM (including Compound Xueshuantong Capsule, Qiming Granule, and others) combined with WM for NPDR could improve the overall effiicacy [n = 1686, RR 1.24 (1.18,1.30), P < 0.00001, I2 = 0%], and reduce the influence of risk factors related to NPDR, such as glycated hemoglobin level [n = 360, MD − 0.85 (− 1.28, − 0.41), P = 0.0001, I2 = 72%], triglyceride (P < 0.00001), and total cholesterol (P = 0.0008). Moreover, no serious adverse events were reported. Conclusion Compared with WM alone, TCM + WM could significantly improve NPDR and also reduce the correlation levels of risk factors, such as hyperglycemia, dyslipidemia. However, the small sample included in the study might lead to a publication bias, and therefore, our results should be treated with caution.

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Association between Hypertension and Epistaxis: Systematic Review and Meta-analysis

Otolaryngology ◽

10.1177/0194599817721445 ◽

2017 ◽

Vol 157 (6) ◽

pp. 921-927 ◽

Cited By ~ 13

Author(s):

Hyun Jin Min ◽

Hyun Kang ◽

Geun Joo Choi ◽

Kyung Soo Kim

Keyword(s):

Systematic Review ◽

Odds Ratio ◽

Observational Studies ◽

Meta Analysis ◽

Statistical Significance ◽

Cochrane Library ◽

Number Needed To Treat ◽

Large Patient ◽

Comprehensive Search ◽

The Impact

Objective Whether there is an association or a cause-and-effect relationship between epistaxis and hypertension is a subject of longstanding controversy. The objective of this systematic review and meta-analysis was to determine the association between epistaxis and hypertension and to verify whether hypertension is an independent risk factor of epistaxis. Data Sources A comprehensive search was performed using the MEDLINE, EMBASE, and Cochrane Library databases. Review Methods The review was performed according to the Meta-analysis of Observational Studies in Epidemiology guidelines and reported using the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Results We screened 2768 unique studies and selected 10 for this meta-analysis. Overall, the risk of epistaxis was significantly increased for patients with hypertension (odds ratio, 1.532 [95% confidence interval (CI), 1.181-1.986]; number needed to treat, 14.9 [95% CI, 12.3-19.0]). Results of the Q test and I2 statistics suggested considerable heterogeneity ([Formula: see text] = 0.038, I2 = 49.3%). The sensitivity analysis was performed by excluding 1 study at a time, and it revealed no change in statistical significance. Conclusion Although this meta-analysis had some limitations, our study demonstrated that hypertension was significantly associated with the risk of epistaxis. However, since this association does not support a causal relationship between hypertension and epistaxis, further clinical trials with large patient populations will be required to determine the impact of hypertension on epistaxis.

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Prevalence of retinopathy in prediabetes: protocol for a systematic review and meta-analysis

BMJ Open ◽

10.1136/bmjopen-2020-040997 ◽

2021 ◽

Vol 11 (1) ◽

pp. e040997

Author(s):

Varo Kirthi ◽

Paul Nderitu ◽

Uazman Alam ◽

Jennifer Evans ◽

Sarah Nevitt ◽

...

Keyword(s):

Systematic Review ◽

Diabetic Retinopathy ◽

Data Extraction ◽

Meta Analysis ◽

International Diabetes Federation ◽

Current Data ◽

Risk Of Bias ◽

Fundus Photography ◽

Primary Data ◽

Cochrane Library

IntroductionThere is growing evidence of a higher than expected prevalence of retinopathy in prediabetes. This paper presents the protocol of a systematic review and meta-analysis of retinopathy in prediabetes. The aim of the review is to estimate the prevalence of retinopathy in prediabetes and to summarise the current data.Methods and analysisThis protocol is developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines. A comprehensive electronic bibliographic search will be conducted in MEDLINE, EMBASE, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Google Scholar and the Cochrane Library. Eligible studies will report prevalence data for retinopathy on fundus photography in adults with prediabetes. No time restrictions will be placed on the date of publication. Screening for eligible studies and data extraction will be conducted by two reviewers independently, using predefined inclusion criteria and prepiloted data extraction forms. Disagreements between the reviewers will be resolved by discussion, and if required, a third (senior) reviewer will arbitrate.The primary outcome is the prevalence of any standard features of diabetic retinopathy (DR) on fundus photography, as per International Clinical Diabetic Retinopathy Severity Scale (ICDRSS) classification. Secondary outcomes are the prevalence of (1) any retinal microvascular abnormalities on fundus photography that are not standard features of DR as per ICDRSS classification and (2) any macular microvascular abnormalities on fundus photography, including but not limited to the presence of macular exudates, microaneurysms and haemorrhages. Risk of bias for included studies will be assessed using a validated risk of bias tool for prevalence studies. Pooled estimates for the prespecified outcomes of interest will be calculated using random effects meta-analytic techniques. Heterogeneity will be assessed using the I2 statistic.Ethics and disseminationEthical approval is not required as this is a protocol for a systematic review and no primary data are to be collected. Findings will be disseminated through peer-reviewed publications and presentations at national and international meetings including Diabetes UK, European Association for the Study of Diabetes, American Diabetes Association and International Diabetes Federation conferences.PROSPERO registration numberCRD42020184820.

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The relationship between migraine and infant colic: A systematic review and meta-analysis

Cephalalgia ◽

10.1177/0333102414534326 ◽

2014 ◽

Vol 35 (1) ◽

pp. 63-72 ◽

Cited By ~ 18

Author(s):

Amy A Gelfand ◽

Peter J Goadsby ◽

I Elaine Allen

Keyword(s):

Systematic Review ◽

Random Effects ◽

Odds Ratio ◽

Fixed Effects ◽

Meta Analysis ◽

Random Effects Model ◽

Fixed Effects Model ◽

Primary Analysis ◽

Infant Colic ◽

The Relationship

Context Infant colic is a common and distressing disorder of early infancy. Its etiology is unknown, making treatment challenging. Several articles have suggested a link to migraine. Objective The objective of this article was to perform a systematic review and, if appropriate, a meta-analysis of the studies on the relationship between infant colic and migraine. Data sources Studies were identified by searching PubMed and ScienceDirect and by hand-searching references and conference proceedings. Study selection For the primary analysis, studies specifically designed to measure the association between colic and migraine were included. For the secondary analysis, studies that collected data on colic and migraine but were designed for another primary research question were also included. Data extraction Data were abstracted from the original studies, through communication with study authors, or both. Two authors independently abstracted data. Main outcomes and measures The main outcome measure was the association between infant colic and migraine using both a fixed-effects model and a more conservative random-effects model. Results Three studies were included in the primary analysis; the odds ratio for the association between migraine and infant colic was 6.5 (4.6–8.9, p < 0.001) for the fixed-effects model and 5.6 (3.3–9.5, p = 0.004) for the random-effects model. In a sensitivity analysis wherein the study with the largest effect size was removed, the odds ratio was 3.6 (95% CI 1.7–7.6, p = 0.001) for both the fixed-effects model and random-effects model. Conclusions In this meta-analysis, infant colic was associated with increased odds of migraine. If infant colic is a migrainous disorder, this would have important implications for treatment. The main limitation of this meta-analysis was the relatively small number of studies included.

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Potential Biomarkers for Post-Stroke Cognitive Impairment: A Systematic Review and Meta-Analysis

International Journal of Molecular Sciences ◽

10.3390/ijms23020602 ◽

2022 ◽

Vol 23 (2) ◽

pp. 602

Author(s):

Ka Young Kim ◽

Ki Young Shin ◽

Keun-A Chang

Keyword(s):

Systematic Review ◽

Uric Acid ◽

Cognitive Impairment ◽

Meta Analysis ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Cochrane Library ◽

Blood Proteins ◽

Post Stroke

Stroke is a primary debilitating disease in adults, occurring in 15 million individuals each year and causing high mortality and disability rates. The latest estimate revealed that stroke is currently the second leading cause of death worldwide. Post-stroke cognitive impairment (PSCI), one of the major complications after stroke, is frequently underdiagnosed. However, stroke has been reported to increase the risk of cognitive impairment by at least five to eight times. In recent decades, peripheral blood molecular biomarkers for stroke have emerged as diagnostic, prognostic, and therapeutic targets. In this study, we aimed to evaluate some blood-derived proteins for stroke, especially related to brain damage and cognitive impairments, by conducting a systematic review and meta-analysis and discussing the possibility of these proteins as biomarkers for PSCI. Articles published before 26 July 2021 were searched in PubMed, Embase, the Web of Science, and the Cochrane Library to identify all relevant studies reporting blood biomarkers in patients with stroke. Among 1820 articles, 40 were finally identified for this study. We meta-analyzed eight peripheral biomarker candidates: homocysteine (Hcy), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), uric acid, and glycated hemoglobin (HbA1c). The Hcy, CRP, TC, and LDL-C levels were significantly higher in patients with PSCI than in the non-PSCI group; however, the HDL-C, TG, uric acid, and HbA1c levels were not different between the two groups. Based on our findings, we suggest the Hcy, CRP, TC, and LDL-C as possible biomarkers in patients with post-stroke cognitive impairment. Thus, certain blood proteins could be suggested as effective biomarkers for PSCI.

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Nervous and Muscular Adverse Events after COVID-19 Vaccination: A Systematic Review and Meta-Analysis of Clinical Trials

Vaccines ◽

10.3390/vaccines9080939 ◽

2021 ◽

Vol 9 (8) ◽

pp. 939

Author(s):

Jiaxin Chen ◽

Yuangui Cai ◽

Yicong Chen ◽

Anthony P. Williams ◽

Yifang Gao ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Adverse Events ◽

Fixed Effects ◽

Meta Analysis ◽

Phase 1 ◽

Cochrane Library ◽

Categorical Variables ◽

Control Group ◽

Open Label

Background: Nervous and muscular adverse events (NMAEs) have garnered considerable attention after the vaccination against coronavirus disease (COVID-19). However, the incidences of NMAEs remain unclear. We aimed to calculate the pooled event rate of NMAEs after COVID-19 vaccination. Methods: A systematic review and meta-analysis of clinical trials on the incidences of NMAEs after COVID-19 vaccination was conducted. The PubMed, Medline, Embase, Cochrane Library, and Chinese National Knowledge Infrastructure databases were searched from inception to 2 June 2021. Two independent reviewers selected the study and extracted the data. Categorical variables were analyzed using Pearson’s chi-square test. The pooled odds ratio (OR) with the corresponding 95% confidence intervals (CIs) were estimated and generated with random or fixed effects models. The protocol of the present study was registered on PROSPERO (CRD42021240450). Results: In 15 phase 1/2 trials, NMAEs occurred in 29.2% vs. 21.6% (p < 0.001) vaccinated participants and controls. Headache and myalgia accounted for 98.2% and 97.7%, and their incidences were 16.4% vs. 13.9% (OR = 1.97, 95% CI = 1.28–3.06, p = 0.002) and 16.0% vs. 7.9% (OR = 3.31, 95% CI = 2.05–5.35, p < 0.001) in the vaccine and control groups, respectively. Headache and myalgia were more frequent in the newly licensed vaccines (OR = 1.97, 95% CI = 1.28–3.06, p = 0.02 and OR = 3.31, 95% CI = 2.05–5.35, p < 0.001) and younger adults (OR = 1.40, 95% CI = 1.12–1.75, p = 0.003 and OR = 1.54, 95% CI = 1.20–1.96, p < 0.001). In four open-label trials, the incidences of headache, myalgia, and unsolicited NMAEs were 38.7%, 27.4%, and 1.5%. Following vaccination in phase 3 trials, headache and myalgia were still common with a rate of 29.5% and 19.2%, although the unsolicited NMAEs with incidence rates of ≤ 0.7% were not different from the control group in each study. Conclusions: Following the vaccination, NMAEs are common of which headache and myalgia comprised a considerable measure, although life-threatening unsolicited events are rare. NMAEs should be continuously monitored during the ongoing global COVID-19 vaccination program.

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The association of fracture risk in atrial fibrillation patients and long-term anticoagulant therapy category: a systematic review and meta-analysis

PeerJ ◽

10.7717/peerj.10683 ◽

2021 ◽

Vol 9 ◽

pp. e10683

Author(s):

Jun Chen ◽

Lingchun Lyu ◽

Jiayi Shen ◽

Chunlai Zeng ◽

Cheng Chen ◽

...

Keyword(s):

Atrial Fibrillation ◽

Systematic Review ◽

Hip Fracture ◽

Fracture Risk ◽

Hip Fractures ◽

Observational Studies ◽

Meta Analysis ◽

Cochrane Library ◽

Hip Fracture Risk ◽

Significant Difference

Objective Our study aimed to assess the risk of all fractures and hip fractures in patients with atrial fibrillation (AF) who took non-vitamin K antagonist oral anticoagulants (NOACs) compared to warfarin. Methods We searched PubMed, Embase, and Cochrane Library and Clinical Trials.gov Website. Reviewed related researches up to January 31, 2020, to identify studies with more than 12 months of follow-up data. The protocol for this systematic review and meta-analysis has been registered in the International Prospective Register of Systematic Reviews (PROSPERO Number: CRD42020156893). Results We included five RCT studies, and five observational studies that contained a total of 326,846 patients in our meta-analysis. Our meta-analysis showed that patients taken NOACs had no significant all fracture risk (RR = 0.91, 95% CI [0.81–1.01]) and hip fracture risk (RR = 0.92, 95% CI [0.82–1.03]) compared with those taken warfarin. Subanalysis showed that the risk of all fractures and hip fractures treated by NOACs were significant lower compared with warfarin in observational studies compared with RCT studies. Also, a subanalysis across the duration of anticoagulation showed the NOACs users have lower all fracture risk than warfarin users when the duration of anticoagulation ≤2 years (RR = 0.89, 95% CI [0.80–0.99]). Further analysis, significant lower all fracture risk in the rivaroxaban therapy (RR = 0.81; 95% CI [0.76–0.86]) compared with warfarin but no statistical significance in hip fracture. There were no significant difference of all fracture risk and hip fracture risk in dabigatran, apixaban, and edoxaban therapy compared with warfarin. Conclusion The meta-analysis demonstrated that NOACs associated with a significantly lower all fracture risk compared with warfarin when the duration of anticoagulation more than 2 years. Rivaroxaban users had lower risk of all fracture than warfarin users in AF patients. But there was no evidence to verify apixaban, edoxaban, and dabigatranin could decrease all fracture and hip fracture risk compared with warfarin.

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