Pub Date : 2024-05-01Epub Date: 2024-05-09DOI: 10.1002/phar.2925
C Michael White, Kimberly Snow Caroti, Youssef Bessada, Adrian V Hernandez, William L Baker, Paul P Dobesh, Heleen van Haalen, Kirsty Rhodes, Craig I Coleman
Previous meta-analyses assessed andexanet alfa (AA) or prothrombin complex concentrate (PCC) products for the treatment of Factor Xa inhibitor (FXaI)-associated major bleeding. However, they did not include recent studies or assess the impact of the risk of bias. We conducted a systematic review with meta-analysis on the effectiveness of AA versus PCC products for FXaI-associated major bleeding, inclusive of the studies' risk of bias. PubMed and Embase were searched for comparative studies assessing major bleeding in patients using FXaI who received AA or PCC. We used the Methodological Index for NOn-Randomized Studies (MINORS) checklist and one question from the Joanna Briggs Institute (JBI) Critical Appraisal of Case Series tool to assess the risk of bias. Random-effects meta-analyses were performed to provide a pooled estimate for the effect of AA versus PCC products on hemostatic efficacy, in-hospital mortality, 30-day mortality, and thrombotic events. Low-moderate risk of bias studies were meta-analyzed separately, as well as combined with high risk of bias studies. Eighteen comparative evaluations of AA versus PCC were identified. Twenty-eight percent of the studies (n = 5) had low-moderate risk and 72% (n = 13) had a high risk of bias. Studies with low-moderate risk of bias suggested improvements in hemostatic efficacy [Odds Ratio (OR) 2.72 (95% Confidence Interval (CI): 1.15-6.44); one study], lower in-hospital mortality [OR 0.48 (95% CI: 0.38-0.61); three studies], and reduced 30-day mortality [OR 0.49 (95% CI: 0.30-0.80); two studies] when AA was used versus PCC products. When studies were included regardless of the risk of bias, pooled effects showed improvements in hemostatic efficacy [OR 1.36 (95% CI: 1.01-1.84); 12 studies] and reductions in 30-day mortality [OR 0.53 (95% CI: 0.37-0.76); six studies] for AA versus PCC. The difference in thrombotic events with AA versus PCC was not statistically significant in the low-moderate, high, or combined risk of bias groups. The evidence from low-moderate quality real-world studies suggests that AA is superior to PCC in enhancing hemostatic efficacy and reducing in-hospital and 30-day mortality. When studies are assessed regardless of the risk of bias, the pooled hemostatic efficacy and 30-day mortality risk remain significantly better with AA versus PCC.
{"title":"Andexanet alfa versus PCC products for factor Xa inhibitor bleeding: A systematic review with meta-analysis.","authors":"C Michael White, Kimberly Snow Caroti, Youssef Bessada, Adrian V Hernandez, William L Baker, Paul P Dobesh, Heleen van Haalen, Kirsty Rhodes, Craig I Coleman","doi":"10.1002/phar.2925","DOIUrl":"10.1002/phar.2925","url":null,"abstract":"<p><p>Previous meta-analyses assessed andexanet alfa (AA) or prothrombin complex concentrate (PCC) products for the treatment of Factor Xa inhibitor (FXaI)-associated major bleeding. However, they did not include recent studies or assess the impact of the risk of bias. We conducted a systematic review with meta-analysis on the effectiveness of AA versus PCC products for FXaI-associated major bleeding, inclusive of the studies' risk of bias. PubMed and Embase were searched for comparative studies assessing major bleeding in patients using FXaI who received AA or PCC. We used the Methodological Index for NOn-Randomized Studies (MINORS) checklist and one question from the Joanna Briggs Institute (JBI) Critical Appraisal of Case Series tool to assess the risk of bias. Random-effects meta-analyses were performed to provide a pooled estimate for the effect of AA versus PCC products on hemostatic efficacy, in-hospital mortality, 30-day mortality, and thrombotic events. Low-moderate risk of bias studies were meta-analyzed separately, as well as combined with high risk of bias studies. Eighteen comparative evaluations of AA versus PCC were identified. Twenty-eight percent of the studies (n = 5) had low-moderate risk and 72% (n = 13) had a high risk of bias. Studies with low-moderate risk of bias suggested improvements in hemostatic efficacy [Odds Ratio (OR) 2.72 (95% Confidence Interval (CI): 1.15-6.44); one study], lower in-hospital mortality [OR 0.48 (95% CI: 0.38-0.61); three studies], and reduced 30-day mortality [OR 0.49 (95% CI: 0.30-0.80); two studies] when AA was used versus PCC products. When studies were included regardless of the risk of bias, pooled effects showed improvements in hemostatic efficacy [OR 1.36 (95% CI: 1.01-1.84); 12 studies] and reductions in 30-day mortality [OR 0.53 (95% CI: 0.37-0.76); six studies] for AA versus PCC. The difference in thrombotic events with AA versus PCC was not statistically significant in the low-moderate, high, or combined risk of bias groups. The evidence from low-moderate quality real-world studies suggests that AA is superior to PCC in enhancing hemostatic efficacy and reducing in-hospital and 30-day mortality. When studies are assessed regardless of the risk of bias, the pooled hemostatic efficacy and 30-day mortality risk remain significantly better with AA versus PCC.</p>","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140899160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Comment on \"Evaluation of the safety and tolerability of intravenous undiluted levetiracetam at a pediatric institution\".","authors":"Yongyi Zhang, Qiushun Zhang, Junchen Zhang","doi":"10.1002/phar.2918","DOIUrl":"https://doi.org/10.1002/phar.2918","url":null,"abstract":"","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Response to comment on \"Evaluation of the safety and tolerability of intravenous undiluted levetiracetam at a pediatric institution\".","authors":"Lily Price, Lisa Garrity, Sarah Stiehl","doi":"10.1002/phar.2919","DOIUrl":"https://doi.org/10.1002/phar.2919","url":null,"abstract":"","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eleonora Camilleri, Mira Ghobreyal, Mettine H. A. Bos, Pieter H. Reitsma, Felix J. M. Van Der Meer, Jesse J. Swen, Suzanne C. Cannegieter, Nienke van Rein
BackgroundMajor bleeding occurs annually in 1%–3% of patients on vitamin K antagonists (VKAs), despite close monitoring. Genetic variants in proteins involved in VKA response may affect this risk.AimTo determine the association of genetic variants (cytochrome P450 enzymes 2C9 [CYP2C9] and 4F2 [CYP4F2], gamma‐glutamyl carboxylase [GGCX]) with major bleeding in VKA users, separately and combined, including vitamin K epoxide reductase complex subunit‐1 (VKORC1).MethodsA case‐cohort study was established within the BLEEDS cohort, which includes 16,570 patients who initiated VKAs between 2012 and 2014. We selected all 326 major bleeding cases that occurred during 17,613 years of follow‐up and a random subcohort of 978 patients. We determined variants in CYP2C9, CYP4F2, GGCX, VKORC1 and evaluated the interaction between variant genotypes. Hazard ratios for major bleeding with 95% confidence intervals (95% CI) were estimated by weighted Cox regression.ResultsGenotype was determined in 256 cases and 783 subcohort members. Phenprocoumon was the most prescribed VKA for both cases and the subcohort (78% and 75%, respectively). Patients with major bleeding were slightly older than subcohort patients. CYP4F2‐TT carriership was associated with a 1.6‐fold (95% CI 0.9–2.8) increased risk of major bleeding compared with CC‐alleles, albeit not statistically significant. For the CYP2C9 and GGCX variants instead, the major bleeding risk was around unity. Carrying at least two variant genotypes in CYP2C9 (poor metabolizer), CYP4F2‐TT, and VKORC1‐AA was associated with a 4.0‐fold (95%CI 1.4–11.4) increased risk, while carriers of both CYP4F2‐TT and VKORC1‐AA had a particularly increased major bleeding risk (hazard ratio 6.7, 95% CI 1.5–29.8) compared with carriers of CC alleles in CYP4F2 and GG in VKORC1. However, the number of major bleeding cases in carriers of multiple variants was few (8 and 5 patients, respectively).ConclusionsCYP4F2 polymorphism was associated with major bleeding, especially in combination with VKORC1 genetic variants. These variants could be considered to further personalize anticoagulant treatment.
{"title":"Genetic polymorphisms and major bleeding risk during vitamin K antagonists treatment: The BLEEDS case‐cohort","authors":"Eleonora Camilleri, Mira Ghobreyal, Mettine H. A. Bos, Pieter H. Reitsma, Felix J. M. Van Der Meer, Jesse J. Swen, Suzanne C. Cannegieter, Nienke van Rein","doi":"10.1002/phar.2923","DOIUrl":"https://doi.org/10.1002/phar.2923","url":null,"abstract":"BackgroundMajor bleeding occurs annually in 1%–3% of patients on vitamin K antagonists (VKAs), despite close monitoring. Genetic variants in proteins involved in VKA response may affect this risk.AimTo determine the association of genetic variants (cytochrome P450 enzymes 2C9 [<jats:italic>CYP2C9</jats:italic>] and 4F2 [<jats:italic>CYP4F2</jats:italic>], gamma‐glutamyl carboxylase [<jats:italic>GGCX</jats:italic>]) with major bleeding in VKA users, separately and combined, including vitamin K epoxide reductase complex subunit‐1 (<jats:italic>VKORC1</jats:italic>).MethodsA case‐cohort study was established within the BLEEDS cohort, which includes 16,570 patients who initiated VKAs between 2012 and 2014. We selected all 326 major bleeding cases that occurred during 17,613 years of follow‐up and a random subcohort of 978 patients. We determined variants in <jats:italic>CYP2C9</jats:italic>, <jats:italic>CYP4F2</jats:italic>, <jats:italic>GGCX</jats:italic>, <jats:italic>VKORC1</jats:italic> and evaluated the interaction between variant genotypes. Hazard ratios for major bleeding with 95% confidence intervals (95% CI) were estimated by weighted Cox regression.ResultsGenotype was determined in 256 cases and 783 subcohort members. Phenprocoumon was the most prescribed VKA for both cases and the subcohort (78% and 75%, respectively). Patients with major bleeding were slightly older than subcohort patients. <jats:italic>CYP4F2</jats:italic>‐TT carriership was associated with a 1.6‐fold (95% CI 0.9–2.8) increased risk of major bleeding compared with CC‐alleles, albeit not statistically significant. For the <jats:italic>CYP2C9</jats:italic> and <jats:italic>GGCX</jats:italic> variants instead, the major bleeding risk was around unity. Carrying at least two variant genotypes in <jats:italic>CYP2C9</jats:italic> (poor metabolizer), <jats:italic>CYP4F2</jats:italic>‐TT, and <jats:italic>VKORC1</jats:italic>‐AA was associated with a 4.0‐fold (95%CI 1.4–11.4) increased risk, while carriers of both <jats:italic>CYP4F2</jats:italic>‐TT and <jats:italic>VKORC1</jats:italic>‐AA had a particularly increased major bleeding risk (hazard ratio 6.7, 95% CI 1.5–29.8) compared with carriers of CC alleles in <jats:italic>CYP4F2</jats:italic> and GG in <jats:italic>VKORC1</jats:italic>. However, the number of major bleeding cases in carriers of multiple variants was few (8 and 5 patients, respectively).Conclusions<jats:italic>CYP4F2</jats:italic> polymorphism was associated with major bleeding, especially in combination with <jats:italic>VKORC1</jats:italic> genetic variants. These variants could be considered to further personalize anticoagulant treatment.","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140827219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jyotirmoy Sarker, Emir Carkovic, Karolina Ptaszek, Todd A Lee
STUDY OBJECTIVE To determine whether there is a signal for gastrointestinal (GI) or intracranial (IC) hemorrhage associated with the use of antiviral medications for influenza in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. DESIGN Disproportionality analysis. DATA SOURCE The FAERS database was searched using OpenVigil 2.1 to identify GI and IC hemorrhage events reported between 2004 and 2022. MEASUREMENTS Antiviral medications for influenza included the following: oseltamivir, zanamivir, peramivir, and baloxavir marboxil. Hemorrhage events were identified using Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries for GI and IC hemorrhages. Reporting odds ratios (RORs) were calculated to compare the occurrence of GI and IC hemorrhage events between antiviral drugs for influenza and (i) all other medications and (ii) antibiotics. RORs were also calculated for each of the individual antiviral medications. MAIN RESULTS A total of 245 cases of GI hemorrhage and 23 cases of IC hemorrhage were identified in association with four antivirals. In comparison with all other drugs, the RORs of GI hemorrhage for oseltamivir, zanamivir, peramivir, baloxavir, and all antivirals combined were 1.17, 0.62, 4.44, 2.53, and 1.22, respectively, indicating potential variations in GI hemorrhage risk among the antivirals. In contrast, in comparison with all other drugs, the RORs of IC hemorrhage for oseltamivir (0.44), zanamivir (0.16), baloxavir (0.44), and all antivirals combined (0.41) were less than 1.0 which is consistent with no elevated risk of IC hemorrhage. CONCLUSION In this study, some signals for GI hemorrhage were observed, particularly for peramivir and baloxavir marboxil. Further investigation is warranted to better understand and evaluate the potential risks of GI hemorrhage associated with antiviral treatments for influenza.
研究目的:确定美国食品和药物管理局(FDA)不良事件报告系统(FAERS)数据库中是否存在与使用抗病毒药物治疗流感相关的胃肠道(GI)或颅内(IC)出血信号。数据来源使用OpenVigil 2.1搜索FAERS数据库,以确定2004年至2022年期间报告的消化道和IC出血事件。测量流感抗病毒药物包括以下药物:奥司他韦、扎那米韦、帕拉米韦和巴洛沙韦马勃西。出血事件通过标准化监管活动医学字典 (MedDRA) 对消化道和内脏出血的查询来确定。计算了报告几率比(ROR),以比较流感抗病毒药物与(i)所有其他药物和(ii)抗生素之间消化道和内腔出血事件的发生率。主要结果共发现 245 例消化道出血和 23 例 IC 出血与四种抗病毒药物有关。与所有其他药物相比,奥司他韦、扎那米韦、帕拉米韦、巴洛沙韦和所有抗病毒药物合计的消化道出血ROR分别为1.17、0.62、4.44、2.53和1.22,表明不同抗病毒药物的消化道出血风险可能存在差异。与此相反,与所有其他药物相比,奥司他韦(0.44)、扎那米韦(0.16)、巴洛沙韦(0.44)和所有抗病毒药物合计(0.41)的 IC 出血 ROR 均小于 1.0,这表明 IC 出血风险并没有升高。为了更好地了解和评估与流感抗病毒治疗相关的消化道出血的潜在风险,有必要进行进一步调查。
{"title":"Antiviral influenza treatments and hemorrhage-related adverse events in the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database.","authors":"Jyotirmoy Sarker, Emir Carkovic, Karolina Ptaszek, Todd A Lee","doi":"10.1002/phar.2920","DOIUrl":"https://doi.org/10.1002/phar.2920","url":null,"abstract":"STUDY OBJECTIVE\u0000To determine whether there is a signal for gastrointestinal (GI) or intracranial (IC) hemorrhage associated with the use of antiviral medications for influenza in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database.\u0000\u0000\u0000DESIGN\u0000Disproportionality analysis.\u0000\u0000\u0000DATA SOURCE\u0000The FAERS database was searched using OpenVigil 2.1 to identify GI and IC hemorrhage events reported between 2004 and 2022.\u0000\u0000\u0000MEASUREMENTS\u0000Antiviral medications for influenza included the following: oseltamivir, zanamivir, peramivir, and baloxavir marboxil. Hemorrhage events were identified using Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries for GI and IC hemorrhages. Reporting odds ratios (RORs) were calculated to compare the occurrence of GI and IC hemorrhage events between antiviral drugs for influenza and (i) all other medications and (ii) antibiotics. RORs were also calculated for each of the individual antiviral medications.\u0000\u0000\u0000MAIN RESULTS\u0000A total of 245 cases of GI hemorrhage and 23 cases of IC hemorrhage were identified in association with four antivirals. In comparison with all other drugs, the RORs of GI hemorrhage for oseltamivir, zanamivir, peramivir, baloxavir, and all antivirals combined were 1.17, 0.62, 4.44, 2.53, and 1.22, respectively, indicating potential variations in GI hemorrhage risk among the antivirals. In contrast, in comparison with all other drugs, the RORs of IC hemorrhage for oseltamivir (0.44), zanamivir (0.16), baloxavir (0.44), and all antivirals combined (0.41) were less than 1.0 which is consistent with no elevated risk of IC hemorrhage.\u0000\u0000\u0000CONCLUSION\u0000In this study, some signals for GI hemorrhage were observed, particularly for peramivir and baloxavir marboxil. Further investigation is warranted to better understand and evaluate the potential risks of GI hemorrhage associated with antiviral treatments for influenza.","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140659532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Warfarin is the only oral anticoagulant recommended in women who are breastfeeding. Although warfarin is a compatible and recommended agent in the postpartum period and during lactation, little is known regarding changes to warfarin dose requirements in this patient population. Here, we report the case of a 40‐year‐old woman who transitioned from enoxaparin monotherapy back to warfarin at 2 months postpartum, while she was breastfeeding. Despite resuming warfarin at her previously therapeutic dose, her international normalized ratio (INR) remained subtherapeutic and required multiple dose increases. She ultimately required a 100% increase in her warfarin dose postpartum, compared to pre‐pregnancy, to achieve a therapeutic INR. This case suggests patients may require higher warfarin doses postpartum, compared to pre‐pregnancy, especially if breastfeeding. Clinicians should closely monitor these patients and adjust warfarin doses as necessary.
{"title":"Warfarin dosage in a postpartum woman while breastfeeding: A case report","authors":"Ellen Uppuluri, Niha Idrees, Nancy Shapiro","doi":"10.1002/phar.2917","DOIUrl":"https://doi.org/10.1002/phar.2917","url":null,"abstract":"Warfarin is the only oral anticoagulant recommended in women who are breastfeeding. Although warfarin is a compatible and recommended agent in the postpartum period and during lactation, little is known regarding changes to warfarin dose requirements in this patient population. Here, we report the case of a 40‐year‐old woman who transitioned from enoxaparin monotherapy back to warfarin at 2 months postpartum, while she was breastfeeding. Despite resuming warfarin at her previously therapeutic dose, her international normalized ratio (INR) remained subtherapeutic and required multiple dose increases. She ultimately required a 100% increase in her warfarin dose postpartum, compared to pre‐pregnancy, to achieve a therapeutic INR. This case suggests patients may require higher warfarin doses postpartum, compared to pre‐pregnancy, especially if breastfeeding. Clinicians should closely monitor these patients and adjust warfarin doses as necessary.","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140625028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elmar R. Alizadeh, Thierry Dervieux, Severine Vermeire, Marla Dubinsky, Geert D'Haens, David Laharie, Andrew Shim, Byron P. Vaughn
BackgroundPatients with Crohn's disease (CD) who lose response to biologics experience reduced quality of life (QoL) and costly hospitalizations. Precision‐guided dosing (PGD) provides a comprehensive pharmacokinetic (PK) profile that allows for biologic dosing to be personalized. We analyzed the cost‐effectiveness of infliximab (IFX) PGD relative to two other dose intensification strategies (DIS).MethodsWe developed a hybrid (Markov and decision tree) model of patients with CD who had a clinical response to IFX induction. The analysis had a US payer perspective, a base case time horizon of 5 years, and a 4‐week cycle length. There were three IFX dosing comparators: PGD; dose intensification based on symptoms, inflammatory markers, and trough IFX concentration (DIS1); and dose intensification based on symptoms alone (DIS2). Patients that failed IFX initiated ustekinumab, followed by vedolizumab, and conventional therapy. Transition probabilities for IFX were estimated from real‐world clinical PK data and interventional clinical trial patient‐level data. All other transition probabilities were derived from published randomized clinical trials and cost‐effectiveness analyses. Utility values were sourced from previous health technology assessments. Direct costs included biologic acquisition and infusion, surgeries and procedures, conventional therapy, and lab testing. The primary outcomes were incremental cost‐effectiveness ratios (ICERs). The robustness of results was assessed via one‐way sensitivity, scenario, and probabilistic sensitivity analyses (PSA).ResultsPGD was the cost‐effective IFX dosing strategy with an ICER of 122,932 $ per quality‐adjusted life year (QALY) relative to DIS1 and dominating DIS2. PGD had the lowest percentage (1.1%) of patients requiring a new biologic through 5 years (8.9% and 74.4% for DIS1 and DIS2, respectively). One‐way sensitivity analysis demonstrated that the cost‐effectiveness of PGD was most sensitive to the time between IFX doses. PSA demonstrated that joint parameter uncertainty had moderate impact on some results.ConclusionsPGD provides clinical and QoL benefits by maintaining remission and avoiding IFX failure; it is the most cost‐effective under conservative assumptions.
{"title":"Simulated cost‐effectiveness of a novel precision‐guided dosing strategy in adult patients with Crohn's disease initiating infliximab maintenance therapy","authors":"Elmar R. Alizadeh, Thierry Dervieux, Severine Vermeire, Marla Dubinsky, Geert D'Haens, David Laharie, Andrew Shim, Byron P. Vaughn","doi":"10.1002/phar.2915","DOIUrl":"https://doi.org/10.1002/phar.2915","url":null,"abstract":"BackgroundPatients with Crohn's disease (CD) who lose response to biologics experience reduced quality of life (QoL) and costly hospitalizations. Precision‐guided dosing (PGD) provides a comprehensive pharmacokinetic (PK) profile that allows for biologic dosing to be personalized. We analyzed the cost‐effectiveness of infliximab (IFX) PGD relative to two other dose intensification strategies (DIS).MethodsWe developed a hybrid (Markov and decision tree) model of patients with CD who had a clinical response to IFX induction. The analysis had a US payer perspective, a base case time horizon of 5 years, and a 4‐week cycle length. There were three IFX dosing comparators: PGD; dose intensification based on symptoms, inflammatory markers, and trough IFX concentration (DIS1); and dose intensification based on symptoms alone (DIS2). Patients that failed IFX initiated ustekinumab, followed by vedolizumab, and conventional therapy. Transition probabilities for IFX were estimated from real‐world clinical PK data and interventional clinical trial patient‐level data. All other transition probabilities were derived from published randomized clinical trials and cost‐effectiveness analyses. Utility values were sourced from previous health technology assessments. Direct costs included biologic acquisition and infusion, surgeries and procedures, conventional therapy, and lab testing. The primary outcomes were incremental cost‐effectiveness ratios (ICERs). The robustness of results was assessed via one‐way sensitivity, scenario, and probabilistic sensitivity analyses (PSA).ResultsPGD was the cost‐effective IFX dosing strategy with an ICER of 122,932 $ per quality‐adjusted life year (QALY) relative to DIS1 and dominating DIS2. PGD had the lowest percentage (1.1%) of patients requiring a new biologic through 5 years (8.9% and 74.4% for DIS1 and DIS2, respectively). One‐way sensitivity analysis demonstrated that the cost‐effectiveness of PGD was most sensitive to the time between IFX doses. PSA demonstrated that joint parameter uncertainty had moderate impact on some results.ConclusionsPGD provides clinical and QoL benefits by maintaining remission and avoiding IFX failure; it is the most cost‐effective under conservative assumptions.","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140592041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Intravenous oxytocin is commonly used for labor induction. However, a consensus on the initial dosing regimen is lac with conflicting research findings and varying guidelines. This study aimed to develop a population kinetic-pharmacodynamic (K-PD) model for oxytocin-induced uterine contractions considering real-world data and relevant influencing factors to establish an optimal starting dosing regimen for intravenous oxytocin.
Methods: This retrospective study included pregnant women who underwent labor induction with intravenous oxytocin at Peking University Third Hospital in 2020. A population K-PD model was developed to depict the time course of uterine contraction frequency (UCF), and covariate screening identified significant factors affecting the pharmacokinetics and pharmacodynamics of oxytocin. Model-based simulations were used to optimize the current starting regimen based on specific guidelines.
Results: Data from 77 pregnant women with 1095 UCF observations were described well by the K-PD model. Parity, cervical dilation, and membrane integrity are significant factors influencing the effectiveness of oxytocin. Based on the model-based simulations, the current regimens showed prolonged onset times and high infusion rates. This study proposed a revised approach, beginning with a rapid infusion followed by a reduced infusion rate, enabling most women to achieve the target UCF within approximately 30 min with the lowest possible infusion rate.
Conclusion: The K-PD model of oxytocin effectively described the changes in UCF during labor induction. Furthermore, it revealed that parity, cervical dilation, and membrane integrity are key factors that influence the effectiveness of oxytocin. The optimal starting dosing regimens obtained through model simulations provide valuable clinical references for oxytocin treatment.
{"title":"Optimal starting dosing regimen of intravenous oxytocin for labor induction based on the population kinetic-pharmacodynamic model of uterine contraction frequency.","authors":"Zhiheng Yu, Rong Chen, Cheng Zhao, Renwei Zhang, Tianyan Zhou, Yangyu Zhao","doi":"10.1002/phar.2911","DOIUrl":"10.1002/phar.2911","url":null,"abstract":"<p><strong>Background: </strong>Intravenous oxytocin is commonly used for labor induction. However, a consensus on the initial dosing regimen is lac with conflicting research findings and varying guidelines. This study aimed to develop a population kinetic-pharmacodynamic (K-PD) model for oxytocin-induced uterine contractions considering real-world data and relevant influencing factors to establish an optimal starting dosing regimen for intravenous oxytocin.</p><p><strong>Methods: </strong>This retrospective study included pregnant women who underwent labor induction with intravenous oxytocin at Peking University Third Hospital in 2020. A population K-PD model was developed to depict the time course of uterine contraction frequency (UCF), and covariate screening identified significant factors affecting the pharmacokinetics and pharmacodynamics of oxytocin. Model-based simulations were used to optimize the current starting regimen based on specific guidelines.</p><p><strong>Results: </strong>Data from 77 pregnant women with 1095 UCF observations were described well by the K-PD model. Parity, cervical dilation, and membrane integrity are significant factors influencing the effectiveness of oxytocin. Based on the model-based simulations, the current regimens showed prolonged onset times and high infusion rates. This study proposed a revised approach, beginning with a rapid infusion followed by a reduced infusion rate, enabling most women to achieve the target UCF within approximately 30 min with the lowest possible infusion rate.</p><p><strong>Conclusion: </strong>The K-PD model of oxytocin effectively described the changes in UCF during labor induction. Furthermore, it revealed that parity, cervical dilation, and membrane integrity are key factors that influence the effectiveness of oxytocin. The optimal starting dosing regimens obtained through model simulations provide valuable clinical references for oxytocin treatment.</p>","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139990848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01Epub Date: 2024-03-14DOI: 10.1002/phar.2912
Kathryn Sine, Thomas Lavoie, Aisling R Caffrey, Vrishali V Lopes, David Dosa, Kerry L LaPlante, Haley J Appaneal
Introduction: There are known disparities in the treatment of infectious diseases. However, disparities in treatment of complicated urinary tract infections (UTIs) are largely uninvestigated.
Objectives: We characterized UTI treatment among males in Veterans Affairs (VA) outpatient settings by age, race, and ethnicity and identified demographic characteristics predictive of recommended first-choice antibiotic therapy.
Methods: We conducted a national, retrospective cohort study of male VA patients diagnosed with a UTI and dispensed an outpatient antibiotic from January 2010 through December 2020. Recommended first-choice therapy for complicated UTI was defined as use of a recommended first-line antibiotic drug choice regardless of area of involvement (ciprofloxacin, levofloxacin, or sulfamethoxazole/trimethoprim) and a recommended duration of 7 to 10 days of therapy. Multivariable models were used to identify demographic predictors of recommended first-choice therapy (adjusted odds ratio [aOR] > 1).
Results: We identified a total of 157,898 males diagnosed and treated for a UTI in the outpatient setting. The average antibiotic duration was 9.4 days (±standard deviation [SD] 4.6), and 47.6% of patients were treated with ciprofloxacin, 25.1% with sulfamethoxazole/trimethoprim, 7.6% with nitrofurantoin, and 6.6% with levofloxacin. Only half of the male patients (50.6%, n = 79,928) were treated with recommended first-choice therapy (first-line drug choice and appropriate duration); 77.6% (n = 122,590) were treated with a recommended antibiotic choice and 65.9% (n = 104,070) with a recommended duration. Age 18-49 years (aOR 1.07, 95% confidence interval [CI] 1.03-1.11) versus age ≥65 years was the only demographic factor predictive of recommended first-choice therapy.
Conclusions: Nearly half of the patients included in this study did not receive recommended first-choice therapies; however, racial and ethnic disparities were not identified. Underutilization of recommended first-choice antibiotic therapy in complicated UTIs continues to be an area of focus for antimicrobial stewardship programs.
{"title":"Exploring variations in recommended first-choice therapy for complicated urinary tract infections in males: Insights from outpatient settings across age, race, and ethnicity.","authors":"Kathryn Sine, Thomas Lavoie, Aisling R Caffrey, Vrishali V Lopes, David Dosa, Kerry L LaPlante, Haley J Appaneal","doi":"10.1002/phar.2912","DOIUrl":"10.1002/phar.2912","url":null,"abstract":"<p><strong>Introduction: </strong>There are known disparities in the treatment of infectious diseases. However, disparities in treatment of complicated urinary tract infections (UTIs) are largely uninvestigated.</p><p><strong>Objectives: </strong>We characterized UTI treatment among males in Veterans Affairs (VA) outpatient settings by age, race, and ethnicity and identified demographic characteristics predictive of recommended first-choice antibiotic therapy.</p><p><strong>Methods: </strong>We conducted a national, retrospective cohort study of male VA patients diagnosed with a UTI and dispensed an outpatient antibiotic from January 2010 through December 2020. Recommended first-choice therapy for complicated UTI was defined as use of a recommended first-line antibiotic drug choice regardless of area of involvement (ciprofloxacin, levofloxacin, or sulfamethoxazole/trimethoprim) and a recommended duration of 7 to 10 days of therapy. Multivariable models were used to identify demographic predictors of recommended first-choice therapy (adjusted odds ratio [aOR] > 1).</p><p><strong>Results: </strong>We identified a total of 157,898 males diagnosed and treated for a UTI in the outpatient setting. The average antibiotic duration was 9.4 days (±standard deviation [SD] 4.6), and 47.6% of patients were treated with ciprofloxacin, 25.1% with sulfamethoxazole/trimethoprim, 7.6% with nitrofurantoin, and 6.6% with levofloxacin. Only half of the male patients (50.6%, n = 79,928) were treated with recommended first-choice therapy (first-line drug choice and appropriate duration); 77.6% (n = 122,590) were treated with a recommended antibiotic choice and 65.9% (n = 104,070) with a recommended duration. Age 18-49 years (aOR 1.07, 95% confidence interval [CI] 1.03-1.11) versus age ≥65 years was the only demographic factor predictive of recommended first-choice therapy.</p><p><strong>Conclusions: </strong>Nearly half of the patients included in this study did not receive recommended first-choice therapies; however, racial and ethnic disparities were not identified. Underutilization of recommended first-choice antibiotic therapy in complicated UTIs continues to be an area of focus for antimicrobial stewardship programs.</p>","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140120260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}