A network meta‐analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype‐based warfarin dosing strategies compared to traditional
What is known and objectives Variations in genotypes were observed in randomized clinical trials (RCTs) that evaluated genotype‐based warfarin dosing. We carried out a network meta‐analysis to assess whether any clinically significant differences exist between RCTs evaluating CYP2C9 with VKORC1, wit...
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| Veröffentlicht in: | Journal of clinical pharmacy and therapeutics 2021-06, Vol.46 (3), p.640-648 |
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| creator | Sridharan, Kannan Sivaramakrishnan, Gowri |
| description | What is known and objectives
Variations in genotypes were observed in randomized clinical trials (RCTs) that evaluated genotype‐based warfarin dosing. We carried out a network meta‐analysis to assess whether any clinically significant differences exist between RCTs evaluating CYP2C9 with VKORC1, with CYP2C9 alone and CYP2C9, VKORC1, with CYP4F2 dosing strategies.
Methods
Electronic records were searched for RCTs comparing genotype‐based warfarin with traditional‐dosing strategies. Key outcomes included were the time to first therapeutic international normalized ratio (INR); time to stable INR or warfarin dose; percent time in therapeutic range (TTR); and the proportion of patients with supra‐therapeutic INR. Weighted mean differences (WMD) and odds ratios (OR) with 95% confidence intervals (95% CI) were the effect estimates.
Results and discussion
Twenty‐six studies (7898 patients) were included. CYP2C9‐based warfarin dosing was associated with a shorter time to first therapeutic INR (WMD: ‐2.73, 95% CI: ‐3.41, ‐2.05) and stable INR/warfarin dose (WMD: ‐8.1, 95% CI: ‐12.54, ‐3.66). CYP2C9 and VKORC1 were observed with a shorter time to first therapeutic INR (WMD: ‐1.92, 95% CI: ‐3.23, ‐0.61) and stable INR/warfarin dose (WMD: ‐4.6, 95% CI: ‐6.87, ‐2.34) along with a longer TTR (%) (WMD: 3.91, 95% CI: 1.18, 6.63). CYP2C9, VKORC1 and CYP4F2 were observed with a reduced proportion of patients with supra‐therapeutic INR (OR: 0.68, 95% CI: 0.49, 0.93). Trial sequential analysis confirms the superior benefits of CYP2C9 with VKORC1 genotype.
What is new and conclusion
The present evidence is supportive of personalizing warfarin dose based only on CYP2C9 and VKORC1 genotypes compared to traditional strategies. More RCTs are needed to delineate any benefit for adding CYP4F2 to provide sufficient power for pooled analysis. No convincing evidence exists supporting the role of CYP2C9 alone.
Studies have shown CYP2C9, VKORC1 and CYP4F2 polymorphisms to influence the clinical pharmacodynamics of warfarin. The present network meta‐analysis confirms the roles of CYP2C9 with VKORC1 but not for additional CYP4F2. |
| doi_str_mv | 10.1111/jcpt.13334 |
| format | Article |
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Variations in genotypes were observed in randomized clinical trials (RCTs) that evaluated genotype‐based warfarin dosing. We carried out a network meta‐analysis to assess whether any clinically significant differences exist between RCTs evaluating CYP2C9 with VKORC1, with CYP2C9 alone and CYP2C9, VKORC1, with CYP4F2 dosing strategies.
Methods
Electronic records were searched for RCTs comparing genotype‐based warfarin with traditional‐dosing strategies. Key outcomes included were the time to first therapeutic international normalized ratio (INR); time to stable INR or warfarin dose; percent time in therapeutic range (TTR); and the proportion of patients with supra‐therapeutic INR. Weighted mean differences (WMD) and odds ratios (OR) with 95% confidence intervals (95% CI) were the effect estimates.
Results and discussion
Twenty‐six studies (7898 patients) were included. CYP2C9‐based warfarin dosing was associated with a shorter time to first therapeutic INR (WMD: ‐2.73, 95% CI: ‐3.41, ‐2.05) and stable INR/warfarin dose (WMD: ‐8.1, 95% CI: ‐12.54, ‐3.66). CYP2C9 and VKORC1 were observed with a shorter time to first therapeutic INR (WMD: ‐1.92, 95% CI: ‐3.23, ‐0.61) and stable INR/warfarin dose (WMD: ‐4.6, 95% CI: ‐6.87, ‐2.34) along with a longer TTR (%) (WMD: 3.91, 95% CI: 1.18, 6.63). CYP2C9, VKORC1 and CYP4F2 were observed with a reduced proportion of patients with supra‐therapeutic INR (OR: 0.68, 95% CI: 0.49, 0.93). Trial sequential analysis confirms the superior benefits of CYP2C9 with VKORC1 genotype.
What is new and conclusion
The present evidence is supportive of personalizing warfarin dose based only on CYP2C9 and VKORC1 genotypes compared to traditional strategies. More RCTs are needed to delineate any benefit for adding CYP4F2 to provide sufficient power for pooled analysis. No convincing evidence exists supporting the role of CYP2C9 alone.
Studies have shown CYP2C9, VKORC1 and CYP4F2 polymorphisms to influence the clinical pharmacodynamics of warfarin. The present network meta‐analysis confirms the roles of CYP2C9 with VKORC1 but not for additional CYP4F2.</description><identifier>ISSN: 0269-4727</identifier><identifier>EISSN: 1365-2710</identifier><identifier>DOI: 10.1111/jcpt.13334</identifier><identifier>PMID: 33346393</identifier><language>eng</language><publisher>England: Hindawi Limited</publisher><subject>Anticoagulants - administration & dosage ; Anticoagulants - pharmacokinetics ; Clinical trials ; Cytochrome P-450 CYP2C9 - genetics ; Cytochrome P450 Family 4 - genetics ; Dosage ; Dose-Response Relationship, Drug ; Drug Monitoring ; Genotype ; Genotype & phenotype ; Genotypes ; Humans ; International Normalized Ratio ; Meta-analysis ; Network Meta-Analysis ; oral anticoagulant ; personalized therapy ; Pharmacogenetics ; pharmacogenomics ; Racial Groups ; Randomized Controlled Trials as Topic ; Vitamin K Epoxide Reductases - genetics ; Warfarin ; Warfarin - administration & dosage ; Warfarin - pharmacokinetics</subject><ispartof>Journal of clinical pharmacy and therapeutics, 2021-06, Vol.46 (3), p.640-648</ispartof><rights>2020 John Wiley & Sons Ltd</rights><rights>2020 John Wiley & Sons Ltd.</rights><rights>Copyright © 2021 John Wiley & Sons Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3574-95b75241cfc01f69fb1bf40233d271699ac3182140d6636ab52a6181fd4d21b43</citedby><cites>FETCH-LOGICAL-c3574-95b75241cfc01f69fb1bf40233d271699ac3182140d6636ab52a6181fd4d21b43</cites><orcidid>0000-0003-3811-6503</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fjcpt.13334$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fjcpt.13334$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,781,785,1418,27926,27927,45576,45577</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33346393$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sridharan, Kannan</creatorcontrib><creatorcontrib>Sivaramakrishnan, Gowri</creatorcontrib><title>A network meta‐analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype‐based warfarin dosing strategies compared to traditional</title><title>Journal of clinical pharmacy and therapeutics</title><addtitle>J Clin Pharm Ther</addtitle><description>What is known and objectives
Variations in genotypes were observed in randomized clinical trials (RCTs) that evaluated genotype‐based warfarin dosing. We carried out a network meta‐analysis to assess whether any clinically significant differences exist between RCTs evaluating CYP2C9 with VKORC1, with CYP2C9 alone and CYP2C9, VKORC1, with CYP4F2 dosing strategies.
Methods
Electronic records were searched for RCTs comparing genotype‐based warfarin with traditional‐dosing strategies. Key outcomes included were the time to first therapeutic international normalized ratio (INR); time to stable INR or warfarin dose; percent time in therapeutic range (TTR); and the proportion of patients with supra‐therapeutic INR. Weighted mean differences (WMD) and odds ratios (OR) with 95% confidence intervals (95% CI) were the effect estimates.
Results and discussion
Twenty‐six studies (7898 patients) were included. CYP2C9‐based warfarin dosing was associated with a shorter time to first therapeutic INR (WMD: ‐2.73, 95% CI: ‐3.41, ‐2.05) and stable INR/warfarin dose (WMD: ‐8.1, 95% CI: ‐12.54, ‐3.66). CYP2C9 and VKORC1 were observed with a shorter time to first therapeutic INR (WMD: ‐1.92, 95% CI: ‐3.23, ‐0.61) and stable INR/warfarin dose (WMD: ‐4.6, 95% CI: ‐6.87, ‐2.34) along with a longer TTR (%) (WMD: 3.91, 95% CI: 1.18, 6.63). CYP2C9, VKORC1 and CYP4F2 were observed with a reduced proportion of patients with supra‐therapeutic INR (OR: 0.68, 95% CI: 0.49, 0.93). Trial sequential analysis confirms the superior benefits of CYP2C9 with VKORC1 genotype.
What is new and conclusion
The present evidence is supportive of personalizing warfarin dose based only on CYP2C9 and VKORC1 genotypes compared to traditional strategies. More RCTs are needed to delineate any benefit for adding CYP4F2 to provide sufficient power for pooled analysis. No convincing evidence exists supporting the role of CYP2C9 alone.
Studies have shown CYP2C9, VKORC1 and CYP4F2 polymorphisms to influence the clinical pharmacodynamics of warfarin. The present network meta‐analysis confirms the roles of CYP2C9 with VKORC1 but not for additional CYP4F2.</description><subject>Anticoagulants - administration & dosage</subject><subject>Anticoagulants - pharmacokinetics</subject><subject>Clinical trials</subject><subject>Cytochrome P-450 CYP2C9 - genetics</subject><subject>Cytochrome P450 Family 4 - genetics</subject><subject>Dosage</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Monitoring</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>Genotypes</subject><subject>Humans</subject><subject>International Normalized Ratio</subject><subject>Meta-analysis</subject><subject>Network Meta-Analysis</subject><subject>oral anticoagulant</subject><subject>personalized therapy</subject><subject>Pharmacogenetics</subject><subject>pharmacogenomics</subject><subject>Racial Groups</subject><subject>Randomized Controlled Trials as Topic</subject><subject>Vitamin K Epoxide Reductases - genetics</subject><subject>Warfarin</subject><subject>Warfarin - administration & dosage</subject><subject>Warfarin - pharmacokinetics</subject><issn>0269-4727</issn><issn>1365-2710</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90d9qFDEUBvAgil2rNz6ABLyR0qk5-Tc7l2VobbXQIlXwashMkjXrzGRMsix75yP4An25Pkmz7uqFF83NgcOPj0M-hF4DOYH83i-7KZ0AY4w_QTNgUhS0BPIUzQiVVcFLWh6gFzEuCSGypOw5OthaySo2Q3eneDRp7cMPPJik7n_9VqPqN9FF7C2uv93QujreT7x26Tv--un6cw1YjfqRNT-neGFGnzaTyZmtikbjtQpWBTdi7aMbFzimoJJZOBNx54dJhWySx3mrXXI-3_ESPbOqj-bVfh6iL-dnt_VFcXX94bI-vSo6JkpeVKItBeXQ2Y6AlZVtobWcUMZ0_glZVapjMKfAiZaSSdUKqiTMwWquKbScHaJ3u9wp-J8rE1MzuNiZvlej8avYUF6CYJSLeaZv_6NLvwr51qwEYwQqQUhWRzvVBR9jMLaZghtU2DRAmm1pzba05k9pGb_ZR67aweh_9G9LGcAOrF1vNo9ENR_rm9td6AMsmqBM</recordid><startdate>202106</startdate><enddate>202106</enddate><creator>Sridharan, Kannan</creator><creator>Sivaramakrishnan, Gowri</creator><general>Hindawi Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3811-6503</orcidid></search><sort><creationdate>202106</creationdate><title>A network meta‐analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype‐based warfarin dosing strategies compared to traditional</title><author>Sridharan, Kannan ; Sivaramakrishnan, Gowri</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3574-95b75241cfc01f69fb1bf40233d271699ac3182140d6636ab52a6181fd4d21b43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Anticoagulants - administration & dosage</topic><topic>Anticoagulants - pharmacokinetics</topic><topic>Clinical trials</topic><topic>Cytochrome P-450 CYP2C9 - genetics</topic><topic>Cytochrome P450 Family 4 - genetics</topic><topic>Dosage</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Monitoring</topic><topic>Genotype</topic><topic>Genotype & phenotype</topic><topic>Genotypes</topic><topic>Humans</topic><topic>International Normalized Ratio</topic><topic>Meta-analysis</topic><topic>Network Meta-Analysis</topic><topic>oral anticoagulant</topic><topic>personalized therapy</topic><topic>Pharmacogenetics</topic><topic>pharmacogenomics</topic><topic>Racial Groups</topic><topic>Randomized Controlled Trials as Topic</topic><topic>Vitamin K Epoxide Reductases - genetics</topic><topic>Warfarin</topic><topic>Warfarin - administration & dosage</topic><topic>Warfarin - pharmacokinetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sridharan, Kannan</creatorcontrib><creatorcontrib>Sivaramakrishnan, Gowri</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of clinical pharmacy and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sridharan, Kannan</au><au>Sivaramakrishnan, Gowri</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A network meta‐analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype‐based warfarin dosing strategies compared to traditional</atitle><jtitle>Journal of clinical pharmacy and therapeutics</jtitle><addtitle>J Clin Pharm Ther</addtitle><date>2021-06</date><risdate>2021</risdate><volume>46</volume><issue>3</issue><spage>640</spage><epage>648</epage><pages>640-648</pages><issn>0269-4727</issn><eissn>1365-2710</eissn><abstract>What is known and objectives
Variations in genotypes were observed in randomized clinical trials (RCTs) that evaluated genotype‐based warfarin dosing. We carried out a network meta‐analysis to assess whether any clinically significant differences exist between RCTs evaluating CYP2C9 with VKORC1, with CYP2C9 alone and CYP2C9, VKORC1, with CYP4F2 dosing strategies.
Methods
Electronic records were searched for RCTs comparing genotype‐based warfarin with traditional‐dosing strategies. Key outcomes included were the time to first therapeutic international normalized ratio (INR); time to stable INR or warfarin dose; percent time in therapeutic range (TTR); and the proportion of patients with supra‐therapeutic INR. Weighted mean differences (WMD) and odds ratios (OR) with 95% confidence intervals (95% CI) were the effect estimates.
Results and discussion
Twenty‐six studies (7898 patients) were included. CYP2C9‐based warfarin dosing was associated with a shorter time to first therapeutic INR (WMD: ‐2.73, 95% CI: ‐3.41, ‐2.05) and stable INR/warfarin dose (WMD: ‐8.1, 95% CI: ‐12.54, ‐3.66). CYP2C9 and VKORC1 were observed with a shorter time to first therapeutic INR (WMD: ‐1.92, 95% CI: ‐3.23, ‐0.61) and stable INR/warfarin dose (WMD: ‐4.6, 95% CI: ‐6.87, ‐2.34) along with a longer TTR (%) (WMD: 3.91, 95% CI: 1.18, 6.63). CYP2C9, VKORC1 and CYP4F2 were observed with a reduced proportion of patients with supra‐therapeutic INR (OR: 0.68, 95% CI: 0.49, 0.93). Trial sequential analysis confirms the superior benefits of CYP2C9 with VKORC1 genotype.
What is new and conclusion
The present evidence is supportive of personalizing warfarin dose based only on CYP2C9 and VKORC1 genotypes compared to traditional strategies. More RCTs are needed to delineate any benefit for adding CYP4F2 to provide sufficient power for pooled analysis. No convincing evidence exists supporting the role of CYP2C9 alone.
Studies have shown CYP2C9, VKORC1 and CYP4F2 polymorphisms to influence the clinical pharmacodynamics of warfarin. The present network meta‐analysis confirms the roles of CYP2C9 with VKORC1 but not for additional CYP4F2.</abstract><cop>England</cop><pub>Hindawi Limited</pub><pmid>33346393</pmid><doi>10.1111/jcpt.13334</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-3811-6503</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Access via Wiley Online Library |
| subjects | Anticoagulants - administration & dosage Anticoagulants - pharmacokinetics Clinical trials Cytochrome P-450 CYP2C9 - genetics Cytochrome P450 Family 4 - genetics Dosage Dose-Response Relationship, Drug Drug Monitoring Genotype Genotype & phenotype Genotypes Humans International Normalized Ratio Meta-analysis Network Meta-Analysis oral anticoagulant personalized therapy Pharmacogenetics pharmacogenomics Racial Groups Randomized Controlled Trials as Topic Vitamin K Epoxide Reductases - genetics Warfarin Warfarin - administration & dosage Warfarin - pharmacokinetics |
| title | A network meta‐analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype‐based warfarin dosing strategies compared to traditional |
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