Ukwuru Therapeutics is an Ukwuru science research journal. It spans all therapeutics research conducted by Ukwuru Science Study Group (USSG), Independent Researchers (IR), and Companies.
Ukw Thera. 2024; 24(10): 1-19. Published Online 2024 October 16
UkwSciID: USThera2
PHARMACOGENETIC TESTING PRIOR TO ADMINISTERING WARFARIN IS SUITABLE FOR PREVENTING ADVERSE EVENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Edmund Ikpechi Ukwuru, and Ejiro Akpevba
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Ukwuru, E.I. and Akpevba, E. (2024). Pharmacogenetic Testing prior to Administering Warfarin is suitable for Preventing Adverse Events a Systematic-Review and Meta-Analysis. Ukwuru Therapeutics, 24(1): 1-19.
Abstract
Background
Warfarin use has been marred by several adverse events. A potential solution to these adverse events was considered to be mitigated by carrying out pharmacogenetic testing to determine the correct dosage that would prevent adverse events. This study was a systematic review and meta-analysis conducted to determine the reliability of evidence surrounding pharmacogenetic testing prior to administering warfarin.
Method
We identified 220 studies from CINAHL, Google Scholar, PubMed, and MEDLINE. Studies were screened in line with the PRISMA checklist and data was extracted based on the PICO framework. Review Manager version 5.4.1 was used for the meta-analysis of studies, odd ratio, risk ratio, and fixed effects analysis was carried out. Significance was tested at <.00001.
Findings
Pharmacogenetic testing is superior to non-pharmacogenetic testing before Warfarin therapy in the prevention of adverse events (p<.00001) but not for achieving TTR and INR.
Conclusion
Pharmacogenetic testing before administering warfarin is ideal to prevent the occurrence of adverse events.
Recommendations
Pharmacogenetic tests should always be conducted before patients are given warfarin, and doses should be adjusted accordingly.
Keywords: FLT3, dual therapy, monotherapy, inhibitors, resistance
Introduction
The anticoagulant Warfarin is one of such synthetic medicines that is commonly administered orally for the management of the activities of vitamin-K within the blood stream. Thus, warfarin is often called vitamin-K antagonist (VKA). Stergiopoulos and Brown, (2014) have identified the use of warfarin for management of thromboembolic events in the last five decades. Warfarin acts by interfering with the activity of vitamin-k epoxide reductase complex subunit 1 (VKORC1). Thus, warfarin is capable of downregulating the expression of hepatic coagulation factors II, VII, IX, and X. Available evidence suggests that warfarin has been highly effective in clinical therapy. According to Gage et al. (2017) there is some complexity associated with administration of warfarin. For example, it has not been determined whether an optimal approach towards administration of warfarin is possible. Akin to this complexity, administering warfarin varies from patient to patient on the basis of response to doses. Different patients based on their sociodemographic factors may present with several health outcomes that are dose-dependent (Kimmel et al., 2013; Liao et al., 2014). Failure to acknowledge these differences can result in adverse outcomes such as thrombosis due to overdosing. This implies that outside the appropriate therapeutic range, there are several negative outcomes that could present. According to Agnelli et al. (2013) the therapeutic range is referred to as the international normalized range (INR) which is between 2 and 3. Hill et al. (2021) stated that warfarin is suitable for lowering arteriovenous and cardiac thrombotic events that could ensue after mechanical valve surgery.
Warfarin has a low therapeutic window that affects the possibility of preventing adverse outcomes due to overdosing. Therefore, it is of necessity to ensure that administration of warfarin should be monitored using the INR of prothrombin time (PT-INR). Also, warfarin dosage must be adjusted until the correct dosage has been attained (Gage et al., 2017). It is essential to determine the pharmacogenetic data of patients and implement it when administering warfarin (Pirmohamed et al., 2018). According to Topkara et al. (2016) genetic guided warfarin dosing may be of meaningful importance for lowering incidences of adverse health outcomes. Goulding et al. (2015) indicated the use of pharmacogenetic testing as a predictor of safer warfarin administration. However, some of the studies used low sample sizes that limited the possibility of generalizing their findings. In response to having studies with low weight, Anderson et al. (2012) had conducted the COUMAGEN-II study to assess two algorithms for warfarin administration; these included, a modified algorithm of IWPC and the dose revisions of the IWPC algorithm. However, the study did not result in a statistically significant outcome. Findings from Dahal et al. (2015) suggested that pharmacogenetic testing was of benefit for better administration of warfarin.
This study was conducted to determine the impact of genetic testing prior to warfarin prescription. The objectives of the meta-analyses was to determine cases of adverse events, the time in the therapeutic range (TTR) in both pharmacogenetic and non-pharmacogenetic based dosing. Also, the effectiveness of pharmacogenetic based dosing compared to non-pharmacogenetic based dosing in relation to international normalised range (INR).
Method
Search Strategy
The PICO research framework was adopted in this study. The population of participants in the various studies that were include, were people above the age of 18 years who had been administered Warfarin with or without genetic testing. Since we were interested in comparing pharmacogenetic testing with no pharmacogenetic testing, the intervention was the former while the comparator was the latter. The outcomes were in line with the objectives of conducting the study; efficacy, adverse events, and time in the therapeutic range (TTR) and the international normalised range (INR).
The process of study search lasted for 45 days. Studies were searched from the following databases; Cumulative Index of Allied Health Literature (CINAHL), Google Scholar, PubMed, and Medical Literature Analysis and Retrieval System Online (MEDLINE). The keywords identified from the research objectives were used to develop the search string.
Keywords and Search String
Key Words
Genetic Testing: “genetics” “gene” “genetic testing” “pharmacogenetics” “pharmacogenetic testing”
Warfarin: “warfarin” “anticoagulant” “vitamin-k inhibitor” “prescription” “administration” “therapy” “treatment”
Search String
An example search string including the key words and the Boolean operators is give below;
(“impact”) AND (“genetic testing” OR “pharmacogenetic testing”) (“warfarin therapy”)
Studies that were identified from the databases were screened based on their titles and abstracts. Afterwards, the eligibility assessment was carried out; those studies that passed the eligibility assessment were then included in the meta-analysis.
The studies that were identified were screened based on their titles and abstracts, they were then assessed for eligibility. Those studies that passed the eligibility assessment were included in the meta-analysis (figure I).
Figure I: PRISMA checklist
In total two hundred and twenty studies were identified from research databases, before the removal of duplicates.
Critical Appraisal
Cochrane Critical Appraisal Skills Program (CASP) was used to evaluate the included studies. CASP is comprised of questions that facilitate determination of the quality of included studies. This is because the tool ensures that the studies are in compliance with the research method used in the study.
Data Extraction and Data Analysis
Data was extracted in line with the PICO framework. Review Manager version 5.4.1 was used for the Meta-analysis of studies. Forest plots were used to make comparison between studies. The left side of the plots was in favour of the intervention while the right side was in favour of the comparison. Chi square analysis was used for assessment of heterogeneity between studies. I square analysis and Z score analysis were employed.
Results
Description of Included Studies
As per the eligibility assessment, all fifteen (15) included studies were randomised controlled trial studies. These studies included; Anderson et al. (2007); Anderson et al. (2012), Burmester et al. (2011); Duan, (2016); Gage et al. (2017); Guo et al. (2020); Jin, (2017); Jonas, (2013); Kimmel, (2013); Lee et al. (2020); Makar-Aušperger et al. (2018); Pengo, (2015); Pirmohamed, (2013); Syn et al. (2018) and Verhoef, (2013). The largest study was Gage et al. (2017) with a total population of 1588 (table I).
Table I: PICO table for characteristics of included Studies
AE = Adverse Events; TTR = time in the therapeutic range; INR = International Normalized Range;
Time in the therapeutic range (TTR) (2.0-3.0) INR (2.0-3.0) range in at least 2 consecutive measurements.
Time in the Therapeutic Range (TTR)
The Meta-analysis for time in the therapeutic range is inconclusive because there is a statistically insignificant difference was obtained. This means that administering warfarin with or without pharmacogenetic testing may or may not affect the time in the therapeutic range. The implication is that health professionals should consider pharmacogenetic testing before administering warfarin; however, they should also be aware that patients may still present with poor time in the therapeutic range.
Figure IIA: Time in the therapeutic range is determined neither by pharmacogenetic testing nor non-pharmacogenetic testing prior to warfarin administration
Figure IIA shows that all the included studies were statistically insignificant, this is evidence by the fact that they all made contact with the line of no significance. Despite the lack of a statistically insignificant outcome, most of the studies were on the side that favour non-pharmacogenetic testing. The level of heterogeneity was low (I2 = 0%) but the difference was also not statistically significant (p=0.73). The black diamond at the bottom made contact with the line of no significance; giving a Z score value (3.14) that is not statistically significant (p=0.002). Hence, the meta-analysis is inconclusive.
In the funnel plots, studies with larger weights are expected to align near the top of the plot while studies with small weights are distributed randomly to give a symmetrical shape of a funnel. Thus in this funnel plot there is evidence of minimal levels of heterogeneity between studies and this could arise for any reasons such as researcher or publisher bias.
Figure IIB: Funnel plots time in the therapeutic range
Figure IIB: The studies by Gage et al (2017); Guo et al (2020); Kimmel (2013(; Primohamed et al (2013); Virhoef et al (2013) are expected near the top of the plot. The clustered studies are Anderson et al (2007); Burmester et al (2011); Pengo (2015); these three studies are likely responsible for the bias because they are also statistically insignificant.
The International Normalised Range (INR)
The meta-analysis is statistically insignificant; hence, it is considered inconclusive. The implication is that carrying out pharmacogenetic testing before administering warfarin is not necessarily a predictor of having a good international normalised range. Hence, health professionals must proceed with caution when administering warfarin, even after genetic testing.
Figure IIIA: Pharmacogenetic testing and non-pharmacogenetic testing are not associated with time to International normalised range
Figure IIIA; only Anderson et al. (2007) is statistically significant because its confidence interval arms did not make contact with the line of no significant effect. All other studies made contact with the line of no significant effect, and crossed into the opposite side. The studies by Burmester et al. (2011) and Lee et al. (2020) had low confidence intervals because if their low study weights. The overall the level of heterogeneity is low and it was statistically significant (p<.00001) with an I2 value of 77%. The meta-analysis was not statistically significant because the black diamond made contact with the line of no significant effect. Hence, the Z score is not significant (p=0.11).
The homogeneity of the studies is minimal, evidenced by the fact that five out of ten studies were overlapping in the forest plot. This is also evidenced in the funnel plot (figure IIIB), most of the studies are within the line of average.
Figure IIIB: Funnel plot international normalised range
Figure IIIB: The studies with the highest weights are aligned near the top; they include, Anderson (2007); Anderson et al (2012); Burmester et al (2011); Gage et al (2017); Guo et al (2020); Kimmel et al (2013); Pirmohamed et al (2013); Syn et al (2018). Studies that show evidence of heterogeneity can be found outside of the lines of confidence interval.
Adverse Effects
The meta-analysis is statistically significant in favour of pharmacogenetic testing. The finding implies that carrying out pharmacogenetic testing before administering warfarin leads to lower cases of adverse events. Hence, health professionals should consider conducting pharmacogenetic testing before administering warfarin.
Figure IVA: Pharmacogentic testing before administering warfarin is associated with fewer Adverse Events
Figure IVA: All the studies compared in this meta-analysis, Anderson, (2007); Burmester et al. (2011); Duan (2016) Gage et al. (2017); Guo et al (2020); Jin (2017); Kimmel (2013) were on the side that favoured genetic testing. Only two of them, Burmester et al. (2011) and Guo et al. (2020) did not make contact with the line of no significant effect. The black diamond at the base did not make contact with the line of no significant effect; hence, a statistically significant effect was obtained in favour of genetic testing. The level of heterogeneity was high I2-93% but it was statistically significant (p<.00001) and the Z score was also significant (p<.00001).
The high level of heterogeneity is evidence in the funnel plot in figure 7. Studies are randomly distributed in a manner that shows evidence of heterogeneity.
Figure IVB: Funnel plot Adverse Events
Figure IVB: The funnel plot shows that there is some level of bias between the studies, the heterogeneity of the studies is high, thus the studies are randomly distributed within the funnel plot and outside the line of confidence internals.
Discussion
Time in the Therapeutic Range
Our findings did not result in a statistically significant outcome; implying that administering warfarin with or without pharmacogenetic testing was unlikely to influence the time in the therapeutic range. Our findings contrast with the findings of Tse et al. (2018) which resulted in a statistically significant difference in favour of carrying out genetic testing before administering warfarin. An observable difference between the findings in this study and the findings in Tse et al. (2018) is associated with the number of included studies, and this may have increased the level of homogeneity between studies. In contrast, we included 15 studies that resulted in high level of heterogeneity. Nonetheless, it is imperative that health professionals should still consider accessing the pharmacogenetic status of patients before administering warfarin, and afterwards, continuous monitoring should be considered. Our findings also contrast with Sanderson et al. (2005) who claimed that genetic testing was ideal, and should be conducted before administering warfarin. The variability between the included studies can also be linked to the various populations. The studies were conducted across different populations. Hence, some patients presented with different outcomes with respect to TTR than others. Future studies may want to consider TTR from a perspective of differences in study region, considering that not enough studies are available for carrying out race or country specific TTR meta-analysis.
The International Normalised Range (INR)
Our finding on INR was not statistically significant. Meaning that the time to reach the recommended INR (INR>4) is not influenced by pharmacogenetic or non-pharmacogenetic testing before administering warfarin. Evidence from other studies such as Sun et al. (2016); Asiimwe et al. (2020) have revealed that pharmacogenetic testing before the administration of warfarin can contribute to improved INR. We argue that the difference between our findings and the findings in Sun et al. (2016) and Asiimwe et al. (2020) can be explained by the level of heterogeneity. Our included studies drew participants from various nationalities. This differences in nationalities may have influenced the outcome of our findings. However, the scarcity of studies makes it more difficult to carryout sub-group analysis with respect to study locations. The study by Kaur et al (2022) accounts for interindividual variations that complicate Warfarin dosing. In contrast to this study, Tang et al (2015) found that dosing algorithms that are based on genotype testing have some level of superiority towards improving the outcome of treatment. We acknowledge that despite obtaining a statistically insignificant outcome, it is ideal to carry out pharmacogenetic testing prior to administering warfarin, in order to achieve a good INR. However, in the event that it is not possible to carry out pharmacogenetic testing, health professionals must ensure that they monitor the patient and adjust dosage accordingly.
Adverse Effects
The finding we obtained was statistically significant. The implication is that carrying out pharmacogenetic testing before administering warfarin is ideal for reducing incidence of adverse events. We draw on the findings of Tse et al. (2018); Sanderson et al. (2005) and Wang et al. (2022) to show similarity and the importance of pharmacogenetic testing for lowering the occurrence of adverse events. It is imperative to consider that the mechanism of action of warfarin can result in debilitating outcomes that may be detrimental to the patient. This study is a more recent validation of available evidence but represents an advancement over existing systematic reviews such as Liao et al (2014); Goulding et al (2014); Sanderson et al (2005); Tse et al (2018) and a host of other studies. This is because more recent research were included in this study and it represents outcomes that are unlike other systematic reviews that did not included a wide range of studies.
Conclusion
This study was a systematic review and meta-analysis conducted to determine the effect of genetic testing and non-genetic testing before the administration of Warfarin. This study was important to confirm the ensuing argument on the importance of genetic testing before the administration of Warfarin as evidenced in a range of randomised controlled trials. Some systematic reviews and meta-analysis were previously carried out to ascertain the benefit of genetic testing, contrasting findings were obtained in this study when compared to some existing studies. In summary this study identified that genetic testing is not superior to non genetic testing in terms of TTR and INR, however it is superior in terms of adverse events. The findings on TTR and INR leave room for the possibility of existing researcher or publication bias, as well as differences in study population, while the finding on adverse events question the possibility that the adverse events are unrelated to Warfarin administration rather than a mere reduction in the possibility of higher occurrence of adverse events when genetic testing is compared to non-genetic testing before Warfarin dosing. In conclusion, administering warfarin with or without genetic testing may not influence TTR and INR, but it is a good predictor of preventing adverse events.
References
Agnelli, G., Buller, H. R., Cohen, A., Curto, M., Gallus, A. S., Johnson, M., Masiukiewicz, U., Pak, R., Thompson, J., Raskob, G. E., Weitz, J. I., & AMPLIFY Investigators (2013). Oral apixaban for the treatment of acute venous thromboembolism. The New England journal of medicine, 369(9), 799–808. https://doi.org/10.1056/NEJMoa1302507
Anderson, J. L., Horne, B. D., Stevens, S. M., Woller, S. C., Samuelson, K. M., Mansfield, J. W., Robinson, M., Barton, S., Brunisholz, K., Mower, C. P., Huntinghouse, J. A., Rollo, J. S., Siler, D., Bair, T. L., Knight, S., Muhlestein, J. B., & Carlquist, J. F. (2012). A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation, 125(16), 1997–2005. https://doi.org/10.1161/CIRCULATIONAHA.111.070920
Anderson, J.L., Horne, B.D., Stevens, S.M., Grove, A.S., Barton, S., Nicholas, Z.P., Kahn, S.F.S., May, H.T., Samuelson, K.M., Muhlestein, J.B., Carlquist, J.F. and the Couma-Gen Investigators. (2007). Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation. Circulation, pp. 2563-2571
Asiimwe, I. G., Zhang, E. J., Osanlou, R., Krause, A., Dillon, C., Suarez-Kurtz, G., Zhang, H., Perini, J. A., Renta, J. Y., Duconge, J., Cavallari, L. H., Marcatto, L. R., Beasly, M. T., Perera, M. A., Limdi, N. A., Santos, P. C. J. L., Kimmel, S. E., Lubitz, S. A., Scott, S. A., Kawai, V. K., … Pirmohamed, M. (2020). Genetic Factors Influencing Warfarin Dose in Black-African Patients: A Systematic Review and Meta-Analysis. Clinical pharmacology and therapeutics, 107(6), 1420–1433. https://doi.org/10.1002/cpt.1755
Burmester, J.K., Berg, R.L., Yale, S.H., Rottscheit, C.M., Glurich, I.E., Schmelzer, J.R. and Caldwell, M.D. (2011). Genetics in Medicine, 13(6), pp. 509-518
Dahal, K., Sharma, S. P., Fung, E., Lee, J., Moore, J. H., Unterborn, J. N., & Williams, S. M. (2015). Meta-analysis of Randomized Controlled Trials of Genotype-Guided vs Standard Dosing of Warfarin. Chest, 148(3), 701–710. https://doi.org/10.1378/chest.14-2947
Duan, L., Zhang, N. and Liu, C., 2016. A randomized controlled study of the VKORC1 and CYP2C9 genotypes in guiding warfarin initial dosing algorithm for pulmonary thromboembolism. Chest, 149(4), p.A519.
Gage, B.F., Bass, A.R., Lin, H., Woller, S.C., Stevens, S.M., Al-Hammadi, N., Li, J., Rodríguez, T., Miller, J.P., McMillin, G.A. and Pendleton, R.C., 2017. Effect of genotype-guided warfarin dosing on clinical events and anticoagulation control among patients undergoing hip or knee arthroplasty: the GIFT randomized clinical trial. Jama, 318(12), pp.1115-1124
Goulding, R., Dawes, D., Price, M., Wilkie, S., & Dawes, M. (2015). Genotype-guided drug prescribing: a systematic review and meta-analysis of randomized control trials. British journal of clinical pharmacology, 80(4), 868–877. https://doi.org/10.1111/bcp.12475
Guo, C., Kuang, Y., Zhou, H., Yuan, H., Pei, Q., Li, J., Jiang, W., Ng, C. M., Chen, X., Huo, Y., Cui, Y., Wang, X., Yu, J., Sun, X., Yu, W., Chen, P., Miao, D., Liu, W., Yu, Z., Ouyang, Z., … Yang, G. (2020). Genotype-Guided Dosing of Warfarin in Chinese Adults: A Multicenter Randomized Clinical Trial. Circulation. Genomic and precision medicine, 13(4), e002602. https://doi.org/10.1161/CIRCGEN.119.002602
Hill, M.A., Kwon, J.H., Gerry, B., Hardy, W.A., Walkowiak, O.A., Kavarana, M.N., Nadig, S.N. and Rajab, T.K. (2021). Immune Privilege of Heart Valves. Front. Immunol. 12:731361. doi: 10.3389/fimmu.2021.731361
Jin, H., Jiang, F., Wei, J., Yao, Y., Yuan, H., Yu, M., Qi, A. and Chai, Y., 2017. CYP2C9 and VKORC1 genotype-guided individualized warfarin therapy in Chinese patients with acute pulmonary thromboembolism: a randomized controlled clinical study. Int J Clin Exp Med, 10(3), pp.5595-602.
Jonas, D. E., Evans, J. P., McLeod, H. L., Brode, S., Lange, L. A., Young, M. L., Shilliday, B. B., Bardsley, M. M., Swinton-Jenkins, N. J., & Weck, K. E. (2013). Impact of genotype-guided dosing on anticoagulation visits for adults starting warfarin: a randomized controlled trial. Pharmacogenomics, 14(13), 1593–1603. https://doi.org/10.2217/pgs.13.145
Kaur, N., Pandey, A., Shafiq, N., Gupta, A., Das, R., Singh, H., Ahluwalia, J. And Malhotra, S. (2022). Genetic and Nongenetic Determinants of Variable Warfarin Dose Requirements: A Report from North India. Public Health Genomics, 25(1-2): 52-60
Kimmel, S. E., French, B., Kasner, S. E., Johnson, J. A., Anderson, J. L., Gage, B. F., Rosenberg, Y. D., Eby, C. S., Madigan, R. A., McBane, R. B., Abdel-Rahman, S. Z., Stevens, S. M., Yale, S., Mohler, E. R., 3rd, Fang, M. C., Shah, V., Horenstein, R. B., Limdi, N. A., Muldowney, J. A., 3rd, Gujral, J., … COAG Investigators (2013). A pharmacogenetic versus a clinical algorithm for warfarin dosing. The New England journal of medicine, 369(24), 2283–2293. https://doi.org/10.1056/NEJMoa1310669
Lee, E.K., Yee, J., Lee, G.Y., Chung, J.E., Seong, J.M., Chang, B.C. and Gwak, H.S. (2020). Genotype-guided warfarin dosing may beneft patients with mechanical aortic valve replacements: randomized controlled study. Scientific Reports, 10(6988), pp. 1-6
Liao, Z., Feng, S., Ling, P., & Zhang, G. (2015). Meta-analysis of randomized controlled trials reveals an improved clinical outcome of using genotype plus clinical algorithm for warfarin dosing. Journal of thrombosis and thrombolysis, 39(2), 228–234. https://doi.org/10.1007/s11239-014-1099-9
Makar-Aušperger, K., Krželj, K., Lovrić Benčić, M., Radačić Aumiler, M., Erdeljić Turk, V. and Božina, N. (2018). Warfarin Dosing According to the Genotype-guided Algorithm is Most Beneficial in Patients With Atrial Fibrillation: A Randomized Parallel Group Trial. Therapeutic Drug Monitoring, 40(3):362-368
Pengo, V., Zambon, C. F., Fogar, P., Padoan, A., Nante, G., Pelloso, M., Moz, S., Frigo, A. C., Groppa, F., Bozzato, D., Tiso, E., Gnatta, E., Denas, G., Padayattil Jose, S., Padrini, R., Basso, D., & Plebani, M. (2015). A Randomized Trial of Pharmacogenetic Warfarin Dosing in Naïve Patients with Non-Valvular Atrial Fibrillation. PloS one, 10(12), e0145318. https://doi.org/10.1371/journal.pone.0145318
Pirmohamed, M., Burnside, G., Eriksson, N., Jorgensen, A. L., Toh, C. H., Nicholson, T., Kesteven, P., Christersson, C., Wahlström, B., Stafberg, C., Zhang, J. E., Leathart, J. B., Kohnke, H., Maitland-van der Zee, A. H., Williamson, P. R., Daly, A. K., Avery, P., Kamali, F., Wadelius, M., & EU-PACT Group (2013). A randomized trial of genotype-guided dosing of warfarin. The New England journal of medicine, 369(24), 2294–2303. https://doi.org/10.1056/NEJMoa1311386
Sanderson, S., Emery, J., & Higgins, J. (2005). CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genetics in medicine : official journal of the American College of Medical Genetics, 7(2), 97–104. https://doi.org/10.1097/01.gim.0000153664.65759.cf
Stergiopoulos, K., & Brown, D. L. (2014). Genotype-guided vs clinical dosing of warfarin and its analogues: meta-analysis of randomized clinical trials. JAMA internal medicine, 174(8), 1330–1338. https://doi.org/10.1001/jamainternmed.2014.2368
Sun, X., Yu, W. Y., Ma, W. L., Huang, L. H., & Yang, G. P. (2016). Impact of the CYP4F2 gene polymorphisms on the warfarin maintenance dose: A systematic review and meta-analysis. Biomedical reports, 4(4), 498–506. https://doi.org/10.3892/br.2016.599
Syn, N. L., Wong, A. L., Lee, S. C., Teoh, H. L., Yip, J. W. L., Seet, R. C., Yeo, W. T., Kristanto, W., Bee, P. C., Poon, L. M., Marban, P., Wu, T. S., Winther, M. D., Brunham, L. R., Soong, R., Tai, B. C., & Goh, B. C. (2018). Genotype-guided versus traditional clinical dosing of warfarin in patients of Asian ancestry: a randomized controlled trial. BMC medicine, 16(1), 104. https://doi.org/10.1186/s12916-018-1093-8
Tang, H. L., Shi, W. L., Li, X. G., Zhang, T., Zhai, S. D., & Xie, H. G. (2015). Limited clinical utility of genotype-guided warfarin initiation dosing algorithms versus standard therapy: a meta-analysis and trial sequential analysis of 11 randomized controlled trials. The pharmacogenomics journal, 15(6), 496–504. https://doi.org/10.1038/tpj.2015.16
Topkara, V. K., Knotts, R. J., Jennings, D. L., Garan, A. R., Levin, A. P., Breskin, A., Castagna, F., Cagliostro, B., Yuzefpolskaya, M., Takeda, K., Takayama, H., Uriel, N., Mancini, D. M., Eisenberger, A., Naka, Y., Colombo, P. C., & Jorde, U. P. (2016). Effect of CYP2C9 and VKORC1 Gene Variants on Warfarin Response in Patients with Continuous-Flow Left Ventricular Assist Devices. ASAIO journal (American Society for Artificial Internal Organs : 1992), 62(5), 558–564. https://doi.org/10.1097/MAT.0000000000000390
Tse, G., Gong, M., Li, G., Wong, S. H., Wu, W. K. K., Wong, W. T., Roever, L., Lee, A. P. W., Lip, G. Y. H., Wong, M. C. S., Liu, T., & International Health Informatics Study (IHIS) Network (2018). Genotype-guided warfarin dosing vs. conventional dosing strategies: a systematic review and meta-analysis of randomized controlled trials. British journal of clinical pharmacology, 84(9), 1868–1882. https://doi.org/10.1111/bcp.13621
Verhoef, T. I., Ragia, G., de Boer, A., Barallon, R., Kolovou, G., Kolovou, V., Konstantinides, S., Le Cessie, S., Maltezos, E., van der Meer, F. J., Redekop, W. K., Remkes, M., Rosendaal, F. R., van Schie, R. M., Tavridou, A., Tziakas, D., Wadelius, M., Manolopoulos, V. G., Maitland-van der Zee, A. H., & EU-PACT Group (2013). A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. The New England journal of medicine, 369(24), 2304–2312. https://doi.org/10.1056/NEJMoa1311388
Wang, D., Yong, L., Zhang, Q., & Chen, H. (2022). Impact of CYP2C19 gene polymorphisms on warfarin dose requirement: a systematic review and meta-analysis. Pharmacogenomics, 23(16), 903–911. https://doi.org/10.2217/pgs-2022-0106
Acknowledgements
We acknowledge the efforts of Ukwuru Science Management team and Ukwuru Science Study Group in bringing this study to reality.
Funding
Funding was provided by Ukwuru Science.
Author Information
Edmund Ikpechi, Ukwuru is the research director at Ukwuru Science Lagos. He works with a number of private organisations and individuals, consulting on public health and biomedical science research. He is also a Management Consultant and holds a Honorary Doctor of Business Administration (DBA) for his expertise in business practices.
Ejiro Akpevba is a researcher affiliated with Department of Optometry, University of Benin.
Corresponding Author
Edmund Ikpechi, Ukwuru
Competing Interests
There are no competing interests for this study.
Rights
The publication is open for public use; credits must be provided by acknowledging the authors of the study.
Cite as
Ukwuru, E.I. and Akpevba, E. (2024). Pharmacogenetic Testing Prior to Administering Warfarin is suitable for Preventing Adverse Events: A Systematic Review and Meta-Analysis. Ukwuru Therapeutics, 24(1): 1-19.
Received: 1 August 2024
Accepted: 1 October 2024
Published: 10 October, 2024
Keywords: Warfarin, Pharmacogenetic testing, Time in the therapeutic range, international normalized range, Adverse events