Association of Oral Anticoagulants and Verapamil or Diltiazem With Adverse Bleeding Events in Patients With Nonvalvular Atrial Fibrillation and Normal Kidney Function
Direct oral anticoagulants (DOACs) are purported to have fewer drug-drug interactions than warfarin. However, potential interactions with coprescribed medications are still a safety concern. Verapamil hydrochloride and diltiazem hydrochloride are combined P-glycoprotein (P-gp) and CYP3A4 inhibitors...
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| description | Direct oral anticoagulants (DOACs) are purported to have fewer drug-drug interactions than warfarin. However, potential interactions with coprescribed medications are still a safety concern. Verapamil hydrochloride and diltiazem hydrochloride are combined P-glycoprotein (P-gp) and CYP3A4 inhibitors and may be associated with increases in the risk of bleeding with DOACs.
To evaluate the risk of bleeding with DOACs and verapamil or diltiazem using an active comparator design.
A comparative effectiveness active comparator cohort study was conducted using US population-based data (2010-2015) analyzed between January 1 and July 15, 2019. Data were obtained on 48 442 patients with nonvalvular atrial fibrillation who had received an index prescription of dabigatran, rivaroxaban, or apixaban between October 19, 2010, through June 30, 2015, with final follow-up on October 1, 2015. Analysis was restricted to individuals with no history of kidney disease who were receiving standard doses of the DOACs.
Patients with initial prescriptions of DOACs who were receiving verapamil or diltiazem were compared with those receiving amlodipine or metoprolol.
Overall and gastrointestinal major, moderate, and minor bleeding using primary or secondary diagnoses. Hazard ratios and 95% CIs were estimated using inverse probability of treatment weights in Cox proportional hazards regression models.
Of the 48 442 patients reviewed, analysis was conducted on 1764 patients receiving DOACs with verapamil or diltiazem compared with 3105 receiving amlodipine and 1793 patients receiving DOACs with verapamil or diltiazem compared with 3224 receiving metoprolol. Depending on the comparison, approximately 60% of the cohort were younger than 65 years and male, which differed by treatment group. Rivaroxaban and apixaban were not associated with increased rates of bleeding for patients receiving verapamil or diltiazem compared with those receiving amlodipine or metoprolol. Among patients receiving dabigatran etexilate, the overall bleeding rate was 52% higher (hazard ratio, 1.52; 95% CI, 1.05-2.20) with verapamil or diltiazem vs amlodipine and 43% higher (hazard ratio, 1.43; 95% CI, 1.02-2.00) vs metoprolol. Bleeding rates for dabigatran with verapamil or diltiazem were higher overall for other bleeding types (244.9 vs 158.4 per 1000 person-years; adjusted hazard ratios of overall GI bleeding: 2.16; 95% CI, 1.30-3.60; minor bleeding: 1.56; 95% CI, 1.07-2.27; and minor GI bleeding: 2.16; 95% CI, 1.2 |
| doi_str_mv | 10.1001/jamanetworkopen.2020.3593 |
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To evaluate the risk of bleeding with DOACs and verapamil or diltiazem using an active comparator design.
A comparative effectiveness active comparator cohort study was conducted using US population-based data (2010-2015) analyzed between January 1 and July 15, 2019. Data were obtained on 48 442 patients with nonvalvular atrial fibrillation who had received an index prescription of dabigatran, rivaroxaban, or apixaban between October 19, 2010, through June 30, 2015, with final follow-up on October 1, 2015. Analysis was restricted to individuals with no history of kidney disease who were receiving standard doses of the DOACs.
Patients with initial prescriptions of DOACs who were receiving verapamil or diltiazem were compared with those receiving amlodipine or metoprolol.
Overall and gastrointestinal major, moderate, and minor bleeding using primary or secondary diagnoses. Hazard ratios and 95% CIs were estimated using inverse probability of treatment weights in Cox proportional hazards regression models.
Of the 48 442 patients reviewed, analysis was conducted on 1764 patients receiving DOACs with verapamil or diltiazem compared with 3105 receiving amlodipine and 1793 patients receiving DOACs with verapamil or diltiazem compared with 3224 receiving metoprolol. Depending on the comparison, approximately 60% of the cohort were younger than 65 years and male, which differed by treatment group. Rivaroxaban and apixaban were not associated with increased rates of bleeding for patients receiving verapamil or diltiazem compared with those receiving amlodipine or metoprolol. Among patients receiving dabigatran etexilate, the overall bleeding rate was 52% higher (hazard ratio, 1.52; 95% CI, 1.05-2.20) with verapamil or diltiazem vs amlodipine and 43% higher (hazard ratio, 1.43; 95% CI, 1.02-2.00) vs metoprolol. Bleeding rates for dabigatran with verapamil or diltiazem were higher overall for other bleeding types (244.9 vs 158.4 per 1000 person-years; adjusted hazard ratios of overall GI bleeding: 2.16; 95% CI, 1.30-3.60; minor bleeding: 1.56; 95% CI, 1.07-2.27; and minor GI bleeding: 2.16; 95% CI, 1.29-3.63). Sensitivity analyses showed consistent results for dabigatran when used with verapamil and diltiazem, with magnitudes ranging from 50% to 100% increased hazard rates and no significant results for apixaban or rivaroxaban.
Current US prescribing information only recommends prescribing changes with dabigatran and P-gp inhibitors with lower kidney function. This study found increased bleeding risk associated with dabigatran when used concomitantly with the P-gp inhibitors verapamil and diltiazem in individuals with normal kidney function. Clinicians and patients may need to consider these drug-drug interactions when choosing oral anticoagulation.</description><identifier>ISSN: 2574-3805</identifier><identifier>EISSN: 2574-3805</identifier><identifier>DOI: 10.1001/jamanetworkopen.2020.3593</identifier><identifier>PMID: 32329770</identifier><language>eng</language><publisher>United States: American Medical Association</publisher><subject>Aged ; Aged, 80 and over ; Anti-Arrhythmia Agents - therapeutic use ; Anticoagulants ; Atrial Fibrillation - complications ; Atrial Fibrillation - drug therapy ; Cardiac arrhythmia ; Comorbidity ; Databases, Factual ; Diltiazem - therapeutic use ; Drug Interactions ; Factor Xa Inhibitors - pharmacokinetics ; Factor Xa Inhibitors - therapeutic use ; Female ; Hemorrhage - chemically induced ; Hemorrhage - epidemiology ; Humans ; Kidney diseases ; Male ; Middle Aged ; Online Only ; Original Investigation ; Pharmacy and Clinical Pharmacology ; Retrospective Studies ; Verapamil - therapeutic use</subject><ispartof>JAMA network open, 2020-04, Vol.3 (4), p.e203593</ispartof><rights>2020. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Copyright 2020 Pham P et al. .</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c451t-db3d2a337e99c8be22a69229c6d4606e404354502247ee1302b7162d176f1f8b3</citedby><cites>FETCH-LOGICAL-c451t-db3d2a337e99c8be22a69229c6d4606e404354502247ee1302b7162d176f1f8b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,864,885,27915,27916</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32329770$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pham, Phuong</creatorcontrib><creatorcontrib>Schmidt, Stephan</creatorcontrib><creatorcontrib>Lesko, Lawrence</creatorcontrib><creatorcontrib>Lip, Gregory Y H</creatorcontrib><creatorcontrib>Brown, Joshua D</creatorcontrib><title>Association of Oral Anticoagulants and Verapamil or Diltiazem With Adverse Bleeding Events in Patients With Nonvalvular Atrial Fibrillation and Normal Kidney Function</title><title>JAMA network open</title><addtitle>JAMA Netw Open</addtitle><description>Direct oral anticoagulants (DOACs) are purported to have fewer drug-drug interactions than warfarin. However, potential interactions with coprescribed medications are still a safety concern. Verapamil hydrochloride and diltiazem hydrochloride are combined P-glycoprotein (P-gp) and CYP3A4 inhibitors and may be associated with increases in the risk of bleeding with DOACs.
To evaluate the risk of bleeding with DOACs and verapamil or diltiazem using an active comparator design.
A comparative effectiveness active comparator cohort study was conducted using US population-based data (2010-2015) analyzed between January 1 and July 15, 2019. Data were obtained on 48 442 patients with nonvalvular atrial fibrillation who had received an index prescription of dabigatran, rivaroxaban, or apixaban between October 19, 2010, through June 30, 2015, with final follow-up on October 1, 2015. Analysis was restricted to individuals with no history of kidney disease who were receiving standard doses of the DOACs.
Patients with initial prescriptions of DOACs who were receiving verapamil or diltiazem were compared with those receiving amlodipine or metoprolol.
Overall and gastrointestinal major, moderate, and minor bleeding using primary or secondary diagnoses. Hazard ratios and 95% CIs were estimated using inverse probability of treatment weights in Cox proportional hazards regression models.
Of the 48 442 patients reviewed, analysis was conducted on 1764 patients receiving DOACs with verapamil or diltiazem compared with 3105 receiving amlodipine and 1793 patients receiving DOACs with verapamil or diltiazem compared with 3224 receiving metoprolol. Depending on the comparison, approximately 60% of the cohort were younger than 65 years and male, which differed by treatment group. Rivaroxaban and apixaban were not associated with increased rates of bleeding for patients receiving verapamil or diltiazem compared with those receiving amlodipine or metoprolol. Among patients receiving dabigatran etexilate, the overall bleeding rate was 52% higher (hazard ratio, 1.52; 95% CI, 1.05-2.20) with verapamil or diltiazem vs amlodipine and 43% higher (hazard ratio, 1.43; 95% CI, 1.02-2.00) vs metoprolol. Bleeding rates for dabigatran with verapamil or diltiazem were higher overall for other bleeding types (244.9 vs 158.4 per 1000 person-years; adjusted hazard ratios of overall GI bleeding: 2.16; 95% CI, 1.30-3.60; minor bleeding: 1.56; 95% CI, 1.07-2.27; and minor GI bleeding: 2.16; 95% CI, 1.29-3.63). Sensitivity analyses showed consistent results for dabigatran when used with verapamil and diltiazem, with magnitudes ranging from 50% to 100% increased hazard rates and no significant results for apixaban or rivaroxaban.
Current US prescribing information only recommends prescribing changes with dabigatran and P-gp inhibitors with lower kidney function. This study found increased bleeding risk associated with dabigatran when used concomitantly with the P-gp inhibitors verapamil and diltiazem in individuals with normal kidney function. Clinicians and patients may need to consider these drug-drug interactions when choosing oral anticoagulation.</description><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Anti-Arrhythmia Agents - therapeutic use</subject><subject>Anticoagulants</subject><subject>Atrial Fibrillation - complications</subject><subject>Atrial Fibrillation - drug therapy</subject><subject>Cardiac arrhythmia</subject><subject>Comorbidity</subject><subject>Databases, Factual</subject><subject>Diltiazem - therapeutic use</subject><subject>Drug Interactions</subject><subject>Factor Xa Inhibitors - pharmacokinetics</subject><subject>Factor Xa Inhibitors - therapeutic use</subject><subject>Female</subject><subject>Hemorrhage - chemically induced</subject><subject>Hemorrhage - epidemiology</subject><subject>Humans</subject><subject>Kidney diseases</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Online Only</subject><subject>Original Investigation</subject><subject>Pharmacy and Clinical Pharmacology</subject><subject>Retrospective Studies</subject><subject>Verapamil - therapeutic use</subject><issn>2574-3805</issn><issn>2574-3805</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNpdUctu1DAUtRCIVqW_gIxYz-BHYscbpFA6gKhaFjyWlpPcTD0k9mA7QeWD-E6cTqkKK1_5npfuQegFJWtKCH21M6NxkH768N3vwa0ZYWTNS8UfoWNWymLFK1I-fjAfodMYd4RkHOVKlE_REWecKSnJMfpdx-hba5L1DvseXwUz4Nol23qznQbjUsTGdfgrBLM3ox2wD_itHZI1v2DE32y6xnU3Q4iA3wwAnXVbfD7DwrMOf8rCt_Mt8NK72Qxzlg24TsFmq41tgh2Gg_9idOnDmP8_2s7BDd5Mrl1Wz9CT3gwRTu_eE_Rlc_757P3q4urdh7P6YtUWJU2rruEdM5xLUKqtGmDMCMWYakVXCCKgIAUvi5IwVkgAyglrJBWso1L0tK8afoJeH3T3UzNC1-bs-SB6H-xowo32xup_N85e662ftaQVk6rKAi_vBIL_MUFMeuen4HJmzYSoeMEqVWaUOqDa4GMM0N87UKKXlvV_LeulZb20nLnPH0a8Z_7tlP8BgpmsIA</recordid><startdate>20200424</startdate><enddate>20200424</enddate><creator>Pham, Phuong</creator><creator>Schmidt, Stephan</creator><creator>Lesko, Lawrence</creator><creator>Lip, Gregory Y H</creator><creator>Brown, Joshua D</creator><general>American Medical Association</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>20200424</creationdate><title>Association of Oral Anticoagulants and Verapamil or Diltiazem With Adverse Bleeding Events in Patients With Nonvalvular Atrial Fibrillation and Normal Kidney Function</title><author>Pham, Phuong ; Schmidt, Stephan ; Lesko, Lawrence ; Lip, Gregory Y H ; Brown, Joshua D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c451t-db3d2a337e99c8be22a69229c6d4606e404354502247ee1302b7162d176f1f8b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Anti-Arrhythmia Agents - therapeutic use</topic><topic>Anticoagulants</topic><topic>Atrial Fibrillation - complications</topic><topic>Atrial Fibrillation - drug therapy</topic><topic>Cardiac arrhythmia</topic><topic>Comorbidity</topic><topic>Databases, Factual</topic><topic>Diltiazem - therapeutic use</topic><topic>Drug Interactions</topic><topic>Factor Xa Inhibitors - pharmacokinetics</topic><topic>Factor Xa Inhibitors - therapeutic use</topic><topic>Female</topic><topic>Hemorrhage - chemically induced</topic><topic>Hemorrhage - epidemiology</topic><topic>Humans</topic><topic>Kidney diseases</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Online Only</topic><topic>Original Investigation</topic><topic>Pharmacy and Clinical Pharmacology</topic><topic>Retrospective Studies</topic><topic>Verapamil - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pham, Phuong</creatorcontrib><creatorcontrib>Schmidt, Stephan</creatorcontrib><creatorcontrib>Lesko, Lawrence</creatorcontrib><creatorcontrib>Lip, Gregory Y H</creatorcontrib><creatorcontrib>Brown, Joshua D</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>JAMA network open</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pham, Phuong</au><au>Schmidt, Stephan</au><au>Lesko, Lawrence</au><au>Lip, Gregory Y H</au><au>Brown, Joshua D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Association of Oral Anticoagulants and Verapamil or Diltiazem With Adverse Bleeding Events in Patients With Nonvalvular Atrial Fibrillation and Normal Kidney Function</atitle><jtitle>JAMA network open</jtitle><addtitle>JAMA Netw Open</addtitle><date>2020-04-24</date><risdate>2020</risdate><volume>3</volume><issue>4</issue><spage>e203593</spage><pages>e203593-</pages><issn>2574-3805</issn><eissn>2574-3805</eissn><abstract>Direct oral anticoagulants (DOACs) are purported to have fewer drug-drug interactions than warfarin. However, potential interactions with coprescribed medications are still a safety concern. Verapamil hydrochloride and diltiazem hydrochloride are combined P-glycoprotein (P-gp) and CYP3A4 inhibitors and may be associated with increases in the risk of bleeding with DOACs.
To evaluate the risk of bleeding with DOACs and verapamil or diltiazem using an active comparator design.
A comparative effectiveness active comparator cohort study was conducted using US population-based data (2010-2015) analyzed between January 1 and July 15, 2019. Data were obtained on 48 442 patients with nonvalvular atrial fibrillation who had received an index prescription of dabigatran, rivaroxaban, or apixaban between October 19, 2010, through June 30, 2015, with final follow-up on October 1, 2015. Analysis was restricted to individuals with no history of kidney disease who were receiving standard doses of the DOACs.
Patients with initial prescriptions of DOACs who were receiving verapamil or diltiazem were compared with those receiving amlodipine or metoprolol.
Overall and gastrointestinal major, moderate, and minor bleeding using primary or secondary diagnoses. Hazard ratios and 95% CIs were estimated using inverse probability of treatment weights in Cox proportional hazards regression models.
Of the 48 442 patients reviewed, analysis was conducted on 1764 patients receiving DOACs with verapamil or diltiazem compared with 3105 receiving amlodipine and 1793 patients receiving DOACs with verapamil or diltiazem compared with 3224 receiving metoprolol. Depending on the comparison, approximately 60% of the cohort were younger than 65 years and male, which differed by treatment group. Rivaroxaban and apixaban were not associated with increased rates of bleeding for patients receiving verapamil or diltiazem compared with those receiving amlodipine or metoprolol. Among patients receiving dabigatran etexilate, the overall bleeding rate was 52% higher (hazard ratio, 1.52; 95% CI, 1.05-2.20) with verapamil or diltiazem vs amlodipine and 43% higher (hazard ratio, 1.43; 95% CI, 1.02-2.00) vs metoprolol. Bleeding rates for dabigatran with verapamil or diltiazem were higher overall for other bleeding types (244.9 vs 158.4 per 1000 person-years; adjusted hazard ratios of overall GI bleeding: 2.16; 95% CI, 1.30-3.60; minor bleeding: 1.56; 95% CI, 1.07-2.27; and minor GI bleeding: 2.16; 95% CI, 1.29-3.63). Sensitivity analyses showed consistent results for dabigatran when used with verapamil and diltiazem, with magnitudes ranging from 50% to 100% increased hazard rates and no significant results for apixaban or rivaroxaban.
Current US prescribing information only recommends prescribing changes with dabigatran and P-gp inhibitors with lower kidney function. This study found increased bleeding risk associated with dabigatran when used concomitantly with the P-gp inhibitors verapamil and diltiazem in individuals with normal kidney function. Clinicians and patients may need to consider these drug-drug interactions when choosing oral anticoagulation.</abstract><cop>United States</cop><pub>American Medical Association</pub><pmid>32329770</pmid><doi>10.1001/jamanetworkopen.2020.3593</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Aged, 80 and over Anti-Arrhythmia Agents - therapeutic use Anticoagulants Atrial Fibrillation - complications Atrial Fibrillation - drug therapy Cardiac arrhythmia Comorbidity Databases, Factual Diltiazem - therapeutic use Drug Interactions Factor Xa Inhibitors - pharmacokinetics Factor Xa Inhibitors - therapeutic use Female Hemorrhage - chemically induced Hemorrhage - epidemiology Humans Kidney diseases Male Middle Aged Online Only Original Investigation Pharmacy and Clinical Pharmacology Retrospective Studies Verapamil - therapeutic use |
| title | Association of Oral Anticoagulants and Verapamil or Diltiazem With Adverse Bleeding Events in Patients With Nonvalvular Atrial Fibrillation and Normal Kidney Function |
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