The Clinical Respiratory Journal
ORIGINAL ARTICLE
Pulmonary embolism is associated with current morphine treatment in patients with deep vein thrombosis Cynthia Wei-Sheng Lee1, Chih-Hsin Muo2, Ji-An Liang3,4, Fung-Chang Sung2,3, Chia-Hung Kao3,5 and Jun-Jun Yeh6,7,8 1 Center for Drug Abuse and Addiction, China Medical University Hospital and College of Medicine, China Medical University, Taichung, Taiwan 2 Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan 3 Graduate Institute of Clinical Medicine Science, College of Medicine, China Medical University, Taichung, Taiwan 4 Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan 5 Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan 6 Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan 7 Chia Nan University of Pharmacy and Science, Tainan, Taiwan 8 Meiho University, Pingtung, Taiwan
Abstract Objectives: This study investigates the relationship between current morphine use and the risk of pulmonary embolism (PE) development in deep vein thrombosis (DVT) patients. Methods: We conducted a population-based nested case-control retrospective analysis using the Longitudinal Health Insurance Database 2000 of Taiwan. A DVT cohort of 3668 patients with no history of PE from 1998 to 2010 and the other cohort of 174 patients who subsequently developed PE were evaluated. Morphine use was designated as ‘current’ if the prescription duration covered the index date or ended within 30 days before the index date. Logistic regression was used to estimate the odds ratios and 95% confidence intervals (CI), and the multivariable model was applied to control for age. Results: Compared with non-morphine users, DVT patients who received morphine within 30 days of the index date had a 4.54-fold (95% CI = 2.30–8.97) chance of developing PE. The risk of PE development increased with an increase in cumulative dosage and in the average dosage of morphine. Conclusion: The incidence of PE in DVT patients in Taiwan is associated with current morphine treatment (≤30 days) and is dependent on dosage. Please cite this paper as: Lee CW-S, Muo C-H, Liang J-A, Sung F-C, Kao C-H and Yeh J-J. Pulmonary embolism is associated with current morphine treatment in patients with deep vein thrombosis. Clin Respir J 2015; 9: 233–237.
manuscript: All authors. The guarantor of the paper, taking responsibility for the integrity of the work as a whole: Chia-Hung Kao. Ethics The study was reviewed and approved by the China Medical University Hospital institutional review board prior to initiation of this retrospective analysis.
Implication statement Compared with non-morphine users, deep vein thrombosis patients who receivedmorphine within 30 days of the index date had a 4.54-fold chance of developing pulmonary embolism. The risk of PE development increased with an increase in cumulative dosage and in the average dosage of morphine.
Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article.
The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Key words deep vein thrombosis – morphine – nested case-control study – pulmonary embolism Correspondence Chia-Hung Kao, MD, Graduate Institute of Clinical Medicine Science, College of Medicine, China Medical University, No. 2, Yuh-Der Road, 40447 Taichung, Taiwan. Tel: +886 4 22052121 (Ext 7412) Fax: +886 4 22336174 email: [email protected]; [email protected] Jun-Jun Yeh, MD, Department of Chest Medicine and Family Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, No. 539, Zhongxiao Road., 600 Chiayi City, Taiwan. Tel: +886 5 2765041 (Ext 5573) Fax: +886 5 2774511 email: [email protected]; [email protected] Received: 19 November 2013 Revision requested: 18 February 2014 Accepted: 02 March 2014 DOI:10.1111/crj.12130 Authorship and contributorship The authors’ individual contributions were as follows. Conception and design: Cynthia Wei-Sheng Lee, Chia-Hung Kao, Jun-Jun Yeh. Administrative support: Chih-Hsin Muo, Fung-Chang Sung. Collection and assembly of data: Cynthia Wei-Sheng Lee, Ji-An Liang, Chia-Hung Kao. Data analysis and interpretation: Cynthia Wei-Sheng Lee, Chia-Hung Kao, Jun-Jun Yeh. Manuscript writing: All authors. Final approval of
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Pulmonary embolism and morphine use
Introduction Pulmonary embolism (PE), caused by venous thromboembolism (VTE) from the lower extremities or locally formed pulmonary artery thrombosis (1), is a relatively common vascular disease and is the underlying cause of a significant number of sudden deaths (2, 3). In the United States, the incidence rate exceeds 1 per 1000 patients, and the mortality rate is >15% in the first 3 months after diagnosis (4), showing that PE is nearly as deadly as acute myocardial infarction (5). The risk factors of PE include prolonged immobilization, surgery, thrombophlebitis, bone fracture of lower limb, estrogen use and pregnancy/postpartum (6). PE is usually a consequence of deep vein thrombosis (DVT) (7) because the venous clot may dislodge and migrate to the lungs. Illicit opioid users are at increased risk of hospital admission for DVT, and aging, being a woman and intravenous delivery all independently increase the risk of developing DVT (8). Morphine has been found to antagonize prostaglandin E1-mediated inhibition of human platelet aggregation (9). Furthermore, morphine may exert its potentiation in platelet aggregation by binding to α2-adrenoceptors in human platelets, thereby reducing intracellular cAMP formation and increasing the activation of phospholipase C and the Na+/H+ exchanger (10). Therefore, morphine might promote the formation of thrombosis by promoting platelet aggregation, resulting in DVT and the ensuing PE. Because DVT patients requiring pain alleviation are often administered morphine, it is important to understand the relationship between morphine use and PE incidence. No epidemiological study has investigated this relationship in Taiwan. To evaluate the potential for morphine-induced PE, we compared the incidence of PE in DVT patients treated with and without morphine using data from the National Health Insurance Research Database (NHIRD) of Taiwan.
Materials and methods For this nested case-control study, we used Taiwan National Health Insurance (NHI) claims records that were accessible in the NHIRD. The universal singlepayer health-care program was instituted on March 1, 1995, and reached a coverage rate of over 99% of Taiwanese residents by 2010. This database contains the data of one million people covered by the Taiwan NHI program; each patient was randomly selected from all beneficiaries in 2000, and includes all outpatient and
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inpatient records from 1996 to 2010. We confirm that all data was de-identified and analyzed anonymously. In addition, this study was also approved by the Ethics Review Board at China Medical University (CMUREC-101-012). We obtained the data of 3668 patients with newly diagnosed DVT [International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) 453.8] for the period 1998–2010 to serve as the DVT cohort for this study. We excluded 55 patients with a history of PE (ICD-9-CM 415.1) prior to the date of their DVT diagnosis. All 174 DVT patients who developed PE before the end of 2010 were designated as the case group, and the date of PE diagnosis was defined as the index date. Eight controls were selected from DVT patients who did not develop PE before the end of 2010 as the control group based on the DVT year and index year of each case. Variables included age, sex, morphine use and comorbidities. Among the comorbidities specified were lower limb injuries (including fracture and surgery, ICD-9-CM 820-821 and 823, and operation codes 81.51-81.54), cancer (ICD-9-CM 140-208), diabetes (ICD-9-CM 250), hyperlipidemia (ICD-9-CM 270), heart failure (ICD-9-CM 428), stroke (ICD9-CM 430-438), atrial fibrillation (ICD-9-CM 427.31) and bedsores (ICD-9-CM 707). All comorbidities were defined before the date of PE diagnosis. We also calculated the duration and dosage of morphine use for each patient. Based on a previous study (11), we defined morphine use as ‘current’ if the prescription duration covered the index date or ended less than, or equal to, 30 days before the index date. Moreover, morphine use was defined as ‘recent’ if the prescription ended 31–180 days before the index date, and morphine use was labeled ‘past’ if the prescription ended more than 180 days prior. All statistical analyses were performed using SAS 9.2 software for windows (SAS Institute, Cary, NC, USA), and the significance level was set at 0.05. The chisquared test was used to assess the categorical variables between the case and control groups. The odds ratio and 95% confidence intervals (95% CIs) for PE were assessed using logistic regression. We also assessed the association between PE and morphine dosage, stratified by the median.
Results Data of 1555 DVT patients were used in this study: 174 patients were assigned to the case group, and 1381 patients were assigned to the control group. PE
The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Lee et al.
Pulmonary embolism and morphine use
Table 1. Demographics between PE and non-PE group in DVT patients
Variable Morphine Age, year
ORIGINAL ARTICLE
Pulmonary embolism is associated with current morphine treatment in patients with deep vein thrombosis Cynthia Wei-Sheng Lee1, Chih-Hsin Muo2, Ji-An Liang3,4, Fung-Chang Sung2,3, Chia-Hung Kao3,5 and Jun-Jun Yeh6,7,8 1 Center for Drug Abuse and Addiction, China Medical University Hospital and College of Medicine, China Medical University, Taichung, Taiwan 2 Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan 3 Graduate Institute of Clinical Medicine Science, College of Medicine, China Medical University, Taichung, Taiwan 4 Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan 5 Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan 6 Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan 7 Chia Nan University of Pharmacy and Science, Tainan, Taiwan 8 Meiho University, Pingtung, Taiwan
Abstract Objectives: This study investigates the relationship between current morphine use and the risk of pulmonary embolism (PE) development in deep vein thrombosis (DVT) patients. Methods: We conducted a population-based nested case-control retrospective analysis using the Longitudinal Health Insurance Database 2000 of Taiwan. A DVT cohort of 3668 patients with no history of PE from 1998 to 2010 and the other cohort of 174 patients who subsequently developed PE were evaluated. Morphine use was designated as ‘current’ if the prescription duration covered the index date or ended within 30 days before the index date. Logistic regression was used to estimate the odds ratios and 95% confidence intervals (CI), and the multivariable model was applied to control for age. Results: Compared with non-morphine users, DVT patients who received morphine within 30 days of the index date had a 4.54-fold (95% CI = 2.30–8.97) chance of developing PE. The risk of PE development increased with an increase in cumulative dosage and in the average dosage of morphine. Conclusion: The incidence of PE in DVT patients in Taiwan is associated with current morphine treatment (≤30 days) and is dependent on dosage. Please cite this paper as: Lee CW-S, Muo C-H, Liang J-A, Sung F-C, Kao C-H and Yeh J-J. Pulmonary embolism is associated with current morphine treatment in patients with deep vein thrombosis. Clin Respir J 2015; 9: 233–237.
manuscript: All authors. The guarantor of the paper, taking responsibility for the integrity of the work as a whole: Chia-Hung Kao. Ethics The study was reviewed and approved by the China Medical University Hospital institutional review board prior to initiation of this retrospective analysis.
Implication statement Compared with non-morphine users, deep vein thrombosis patients who receivedmorphine within 30 days of the index date had a 4.54-fold chance of developing pulmonary embolism. The risk of PE development increased with an increase in cumulative dosage and in the average dosage of morphine.
Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article.
The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Key words deep vein thrombosis – morphine – nested case-control study – pulmonary embolism Correspondence Chia-Hung Kao, MD, Graduate Institute of Clinical Medicine Science, College of Medicine, China Medical University, No. 2, Yuh-Der Road, 40447 Taichung, Taiwan. Tel: +886 4 22052121 (Ext 7412) Fax: +886 4 22336174 email: [email protected]; [email protected] Jun-Jun Yeh, MD, Department of Chest Medicine and Family Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, No. 539, Zhongxiao Road., 600 Chiayi City, Taiwan. Tel: +886 5 2765041 (Ext 5573) Fax: +886 5 2774511 email: [email protected]; [email protected] Received: 19 November 2013 Revision requested: 18 February 2014 Accepted: 02 March 2014 DOI:10.1111/crj.12130 Authorship and contributorship The authors’ individual contributions were as follows. Conception and design: Cynthia Wei-Sheng Lee, Chia-Hung Kao, Jun-Jun Yeh. Administrative support: Chih-Hsin Muo, Fung-Chang Sung. Collection and assembly of data: Cynthia Wei-Sheng Lee, Ji-An Liang, Chia-Hung Kao. Data analysis and interpretation: Cynthia Wei-Sheng Lee, Chia-Hung Kao, Jun-Jun Yeh. Manuscript writing: All authors. Final approval of
233
Pulmonary embolism and morphine use
Introduction Pulmonary embolism (PE), caused by venous thromboembolism (VTE) from the lower extremities or locally formed pulmonary artery thrombosis (1), is a relatively common vascular disease and is the underlying cause of a significant number of sudden deaths (2, 3). In the United States, the incidence rate exceeds 1 per 1000 patients, and the mortality rate is >15% in the first 3 months after diagnosis (4), showing that PE is nearly as deadly as acute myocardial infarction (5). The risk factors of PE include prolonged immobilization, surgery, thrombophlebitis, bone fracture of lower limb, estrogen use and pregnancy/postpartum (6). PE is usually a consequence of deep vein thrombosis (DVT) (7) because the venous clot may dislodge and migrate to the lungs. Illicit opioid users are at increased risk of hospital admission for DVT, and aging, being a woman and intravenous delivery all independently increase the risk of developing DVT (8). Morphine has been found to antagonize prostaglandin E1-mediated inhibition of human platelet aggregation (9). Furthermore, morphine may exert its potentiation in platelet aggregation by binding to α2-adrenoceptors in human platelets, thereby reducing intracellular cAMP formation and increasing the activation of phospholipase C and the Na+/H+ exchanger (10). Therefore, morphine might promote the formation of thrombosis by promoting platelet aggregation, resulting in DVT and the ensuing PE. Because DVT patients requiring pain alleviation are often administered morphine, it is important to understand the relationship between morphine use and PE incidence. No epidemiological study has investigated this relationship in Taiwan. To evaluate the potential for morphine-induced PE, we compared the incidence of PE in DVT patients treated with and without morphine using data from the National Health Insurance Research Database (NHIRD) of Taiwan.
Materials and methods For this nested case-control study, we used Taiwan National Health Insurance (NHI) claims records that were accessible in the NHIRD. The universal singlepayer health-care program was instituted on March 1, 1995, and reached a coverage rate of over 99% of Taiwanese residents by 2010. This database contains the data of one million people covered by the Taiwan NHI program; each patient was randomly selected from all beneficiaries in 2000, and includes all outpatient and
234
Lee et al.
inpatient records from 1996 to 2010. We confirm that all data was de-identified and analyzed anonymously. In addition, this study was also approved by the Ethics Review Board at China Medical University (CMUREC-101-012). We obtained the data of 3668 patients with newly diagnosed DVT [International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) 453.8] for the period 1998–2010 to serve as the DVT cohort for this study. We excluded 55 patients with a history of PE (ICD-9-CM 415.1) prior to the date of their DVT diagnosis. All 174 DVT patients who developed PE before the end of 2010 were designated as the case group, and the date of PE diagnosis was defined as the index date. Eight controls were selected from DVT patients who did not develop PE before the end of 2010 as the control group based on the DVT year and index year of each case. Variables included age, sex, morphine use and comorbidities. Among the comorbidities specified were lower limb injuries (including fracture and surgery, ICD-9-CM 820-821 and 823, and operation codes 81.51-81.54), cancer (ICD-9-CM 140-208), diabetes (ICD-9-CM 250), hyperlipidemia (ICD-9-CM 270), heart failure (ICD-9-CM 428), stroke (ICD9-CM 430-438), atrial fibrillation (ICD-9-CM 427.31) and bedsores (ICD-9-CM 707). All comorbidities were defined before the date of PE diagnosis. We also calculated the duration and dosage of morphine use for each patient. Based on a previous study (11), we defined morphine use as ‘current’ if the prescription duration covered the index date or ended less than, or equal to, 30 days before the index date. Moreover, morphine use was defined as ‘recent’ if the prescription ended 31–180 days before the index date, and morphine use was labeled ‘past’ if the prescription ended more than 180 days prior. All statistical analyses were performed using SAS 9.2 software for windows (SAS Institute, Cary, NC, USA), and the significance level was set at 0.05. The chisquared test was used to assess the categorical variables between the case and control groups. The odds ratio and 95% confidence intervals (95% CIs) for PE were assessed using logistic regression. We also assessed the association between PE and morphine dosage, stratified by the median.
Results Data of 1555 DVT patients were used in this study: 174 patients were assigned to the case group, and 1381 patients were assigned to the control group. PE
The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Lee et al.
Pulmonary embolism and morphine use
Table 1. Demographics between PE and non-PE group in DVT patients
Variable Morphine Age, year
