||Pharmacoepidemiologic Research for Ischemic Stroke in Elderly Patients Who Taking Cyclo-oxygenase-2 inhibitors or Conventional Non-steroidal Anti-inflammatory Drugs
||Institute of Biopharmaceutical Sciences
研究結果：在效度分析部分，自全民健保資料庫共定義出372位患者，其中有364位(97.85%)經由放射線檢查報告及臨床表現確認為因栓塞性中風而入院。以主診斷碼計算之陽性預測值(PPV)為0.98，若包含次診斷之陽性預測值為0.87。而所計算所有的共病症之診斷符合率為48.39%；在個別的共病症中陽性預測值分佈範圍較廣從骨折0.50至結腸癌1.00。出院後第一次門診aspirin處方的陽性預測值較高為0.94，而住院期間的aspirin處方則為0.88。研究老年人使用非類固醇抗發炎劑及選擇性第二型環氧酶抑制劑與中風危險之相關性部分，共納入43,214位為世代追蹤的族群，其中10,238位病例組並且配對出至少有一位的對照組。在基本特質部分，病例組之心血管疾病發生率高於對照組，並且在指標日期正在使用非類固醇抗發炎劑的比例亦較高，分別為4,391 (42.9%)及9,399 (32.8%)。而與過去曾使用者比較，除了celecoxib外，所有正在使用非類固醇抗發炎劑的患者具有較高栓塞性中風復發的機率(OR=1.09，95% CI 0.91 to 1.31)，其中以rofecoxib的危險性最高(OR=2.44，95% CI 1.87 to 3.18)，其次為diclofenac (OR=1.83，95% CI 1.40 to 2.38)。無論是否併用aspirin，rofecoxib (OR=2.98， 95% CI 1.59 to 5.59)及diclofenac (OR=1.83，95% CI 1.40 to 2.38)皆具有相同的危險性；相對的naproxen (OR=1.61，95% CI 0.81 to 3.19)及ibuprofen (OR=1.55，95% CI 0.96 to 2.52)在併用aspirin時其危險性並不具統計學上之差異。且經由多項敏感性分析確認本研究結果。
Background: An increased risk of cardiovascular events with non-steroid anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 (COX-2) inhibitors were evident in the literature, which have placed the risk-benefit profile of these COX-2 inhibitors under public scrutiny and two COX-2 inhibitors subsequently been withdrawn from the market. As a result, clinicians have been encouraged to weigh the potential benefits and risks of the NSAIDs prior to prescribing them. Nonetheless, aspirin interaction with other NSAIDs has become new concerns recently. Despite a growing body of literature in this area, very few studies have specifically aimed to examine stroke risk of selective COX-2 inhibitors and NSAIDs in the elderly population in Taiwan. Additionally, the risk resulting from interaction between aspirin, indicated to prevent stroke, and NSAIDs is lacking. Furthermore, although National Health Insurance Research database (NHIRD) provides the longitudinal population data to assess treatment outcomes and drug-disease associations in Taiwan, the data quality of NHIRD has not been systematically evaluated yet.
Objectives: Our study aimed to evaluate the validity of the National Insurance Health Research Database (NHIRD) database in patients with a principal diagnosis of ischemic stroke; to examine the risks of recurrent ischemic stroke among the elderly patients using selective COX-2 inhibitors and other non-steroid anti-inflammatory drugs (NSAIDs); and to investigate the interaction between aspirin and NSAIDs might affect the stroke protective effect of aspirin.
Methods: We conducted a cross-sectional study to evaluate the data quality of NHIRD. This cross-sectional study compares records in NHIRD with those in one medical center. Patients hospitalized for ischemic stroke in 1999 were identified from the two databases. The discharge notes, laboratory data, and medication orders during admission and the first discharge visit were reviewed to validate ischemic stroke diagnoses and aspirin prescribing in NHIRD. Agreement between the two databases in comorbidity of ischemic stroke diagnosis was evaluated using ICD-9 codes. Second, we conducted a retrospective nested case-control study using data from the NHIRD to investigate risk of incident stroke association between NSAIDs/COX-2 inhibitors use and interaction between NSAIDs and aspirin on stroke risk. We identified individuals aged 65 years or older, who were first time hospitalized with ischemic stroke during 1 Jan 2000 to 31 Dec 2003 and who were prescribed any NSAID after discharge. Cases of re-admissions with a major diagnosis of stroke were risk-set matched with three controls for age, sex, calendar year and follow up duration. Current exposure of NSAIDs/coxibs was compared with remote exposure to any NSAIDs. To analyze the effect of NSAIDs on odds of stroke, we employed stratified analyses by aspirin use to evaluate whether NSAIDs/ COX-2 inhibitors antagonize the antiplatelet effects of aspirin. In order to robust our findings, several sensitivity analyses were conducted in this study. Conditional logistic regression models with controlling for all covariates were used to analyze the association between exposure and outcome. All analyses were performed with SAS for Windows, version 9.1.
Results: 372 cases were identified from NHIRD; among them, 364 cases (97.85%) were confirmed as ischemic stroke by radiology examination and clinical presentation. The Positive Predict Value (PPV) was 0.98 among records with this diagnosis in the principle record position and 0.87 in other record positions. The overall agreement of comorbid diagnoses between the two databases was 48.39%. The PPV for selected conditions also varied widely, from 0.50 for fracture to 1.00 for colon cancer. The accuracy of recorded aspirin prescriptions was higher in first post-discharge visits (PPV=0.94) than during hospitalization (PPV=0.88). There were 43,214 patients fulfilled the cohort definition, and 10,238 cases identified with at least 1 matched control were included in the final analysis. As expected, the prevalence of previous cardiovascular admission, and drug use was uniformly increased in cases. A total of 4,391 (42.9%) cases and 9,399 (32.8%) controls had been currently exposed to any NSAIDs before their index date. All current use of NSAIDs, but not celecoxib (OR=1.09, 95% CI 0.91 to 1.31) were associated with higher stroke odds compared with remote users. The risk of ischemic stroke was highest in subjects prescribed rofecoxib (OR=2.44, 95% CI 1.87 to 3.18) followed by diclofenac (OR=1.83, 95% CI 1.63 to 2.05). Both rofecoxib (OR=2.98, 95% CI 1.59 to 5.59) and diclofenac (OR=1.83, 95% CI 1.40 to 2.38) were associated with a statistically significant increase in odds of ischemic stroke, compared with remote users whatever concomitant use of aspirin. In contrast, patients receiving aspirin, naproxen (OR=1.61, 95% CI 0.81 to 3.19) and ibuprofen (OR=1.55, 95% CI 0.96 to 2.52) were not associated with higher rate of ischemic stroke than remote users. Several sensitivity analyses did confirm our findings.
Conclusions: The accuracy of NHIRD in recording ischemic stroke diagnoses and aspirin prescriptions was high, and NHIRD appears to be a valid resource for population research in ischemic stroke. In elderly population, we found a greater risk of ischemic stroke with current use of non-selective NSAIDs and rofecoxib but not celecoxib compared with remote use of any NSAIDs. In those using aspirin, NSAIDs/COX-2 inhibitors, other than celecoxib, naproxen, and ibuprofen, were associated with increased risk of stroke. Additional randomized controlled study is needed to determine the clinical impact of using NSAIDs along with aspirin for stroke prevention.
Chapter 1 Introduction 1
1.1 Statement of Problem 1
1.2 Specific Aims 3
1.3 Significance of This Study 4
Chapter 2 Literature Review 5
2.1 Mechanism of NSAIDs 5
2.1.2 Classification of NSAIDs 8
2.2 Research on NSAIDs Relative Cardiovascular Adverse Effects 12
2.2.1 Mechanism 13
2.2.2 Myocardial infarction 14
2.2.3 Stroke 22
2.3 NSAIDs and Aspirin Interaction 23
2.3.1 Mechanism 23
2.3.2 Clinical data 24
2.4 Clinical Data in Taiwan 25
2.4.1 NSAIDs relative GI complications 26
2.4.2 NSAIDs relative CV complications 27
2.4.3 Pharmaceutical reimbursement guideline 27
2.5 Introduction of NHIRD in Taiwan 28
2.5.1 Background 28
2.5.2 Data protection 28
2.5.3 Structure of NHIRD 29
2.6 Summary of Literature Review 30
Chapter 3 Objectives and hypothesis 31
Chapter 4 Methods 32
4.1 Validation Study 32
4.1.1 Data sources and record linkage 32
4.1.2 Validating diagnoses of ischemic stroke 33
4.1.3 Agreement of comorbid conditions 33
4.1.4 Validity of aspirin exposure 34
4.1.5 Statistical analysis 34
4.2 NSAIDs and Coxibs relative Stroke adverse effect 36
4.2.1 Study design 36
4.2.2 Data source and material 36
4.2.3 Study population and procedure 37
4.2.4 Case definition and exclusion criteria 38
4.2.5 Exposure definition 38
4.2.6 Statistical analysis 39
4.3 Interaction between Aspirin and NSAIDs/coxibs 42
4.3.1 Aspirin exposure definition 42
4.3.2 Statistical analysis 42
4.4 Sensitivity study 42
Chapter 5 Results 44
5.1 Validation study 44
5.2 NSAIDs and Coxibs relative stroke adverse effect 47
5.3 Interaction between aspirin and NSAIDs/Coxibs 48
5.4 Sensitivity study 49
Chapter 6 Discussions 51
6.1 Validation study 51
6.2 NSAIDs and Coxibs relative stroke adverse effect 53
6.3 Interaction between aspirin and NSAIDs/Coxibs 56
Chapter 7 Strength and clinical implication 58
Chapter 8 limitations 60
8.1 Validation study 60
8.2 NSAIDs and Coxibs relative stroke adverse effect 61
Chapter 9 Conclusions 63
Appendix I ATC code for NSAIDs 90
Appendix II Covariance 91
Appendix III Ethical approval documentation for validation study 92
Index of Table
Table 1 Classification of NSAIDs based on chemical categories 9
Table 2 Classification of NSAIDs by COX-1/COX2 selectivity 12
Table 3 Meta-analysis of observational studies reporting on cardiovascular risks with cyclooxygenase 2 inhibitors 20
Table 4 Meta-analysis of observational studies reporting on cardiovascular risks with non-selective NSAIDs 21
Table 5 Dataset and description on NHIRD in Taiwan 29
Table 6 Agreement in Comorbid Conditions between NHIRD and DNMC, with the Latter as Gold Standard 46
Table 7 Baseline characteristics of cases and matched controls 65
Table 8 Characteristics of controls currently exposed to an individual NSAID (n=28643) 66
Table 9 Characteristics of cases currently exposed to an individual NSAID (N=10238) 67
Table 10 Characteristics of cases and matched controls (uni-variate analysis) 70
Table 11 Multiple-variate analysis of cases and matched controls 71
Table 12 Risk of ischemic stroke with use of NSAIDs compared with remote use of a NSAID 72
Table 13 Risk of ischemic stroke and NSAIDs compared with remote use of a NSAID 74
Table 14 Risk of ischemic stroke with use of NSAIDs compared with remote use of a NSAID 75
Table 15 Sensitivity study (current NSAIDs definition as 0 days) 76
Table 16 Sensitivity study (current NSAIDs definition as 7 days) 77
Table 17 Sensitivity study (current NSAIDs definition as 14 days) 78
Table 18 Sensitivity study (include mortality cases) 79
Table 19 Sensitivity study (restrict follow until 2004) 80
Table 20 Sensitivity study (current use of preferential and non-selective NSAIDs) 81
Table 21 Sensitivity study (aspirin cohort) 82
Index of Figure
Figure 1 Production and Actions of Prostaglandins and Thromboxane 7
Figure 2 Concentrations of NSAIDs required inhibiting the activity of COX-1 and COX-2 by 50 Percent (IC50) in assays of whole blood 10
Figure 3 Schematic picture of the active sites of COX-1 and COX-2 10
Figure 4 Determinable log [IC80 ratio (WHMA-COX-2yCOX-1)] for NSAIDs 11
Figure 5 Effect of NSAIDs and coxibs on platelet-active prostanoids 14
Figure 6 Meta-analysis of randomized trials to compared the effects of different selective COX 2 inhibitors versus placebo on vascular events, myocardial infarction, stroke, and vascular death 18
Figure 7 Meta-analysis of randomized trials to compared the effects of different selective COX 2 inhibitors versus other NSAIDs on vascular events, myocardial infarction, stroke, and vascular death 19
Figure 8 Mechanism of interaction between ibuprofen and aspirin 24
Figure 9 Flow chart of validation study 35
Figure 10 Procedure of Database linkage 40
Figure 11 Flow chart of association with NSAIDs and stroke study 41
Figure 12 Distribution of follow up duration among cases 63
Figure 13 Risk of Ischemic Stroke associated with Interaction between NSAIDs and Aspirin 73
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