Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inh
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《英国医生杂志》
1 Institution 13th floor, Tower Building, University Park, Nottingham NG2 7RD
Correspondence to: J Hippisley-Cox Julia.hippisley-cox@nottingham.ac.uk
Aims To determine the comparative risk of myocardial infarction in patients taking cyclo-oxygenase-2 and other non-steroidal anti-inflammatory drugs (NSAIDs) in primary care between 2000 and 2004; to determine these risks in patients with and without pre-existing coronary heart disease and in those taking and not taking aspirin.
Design Nested case-control study.
Setting 367 general practices contributing to the UK QRESEARCH database and spread throughout every strategic health authority and health board in England, Wales, and Scotland.
Subjects 9218 cases with a first ever diagnosis of myocardial infarction during the four year study period; 86 349 controls matched for age, calendar year, sex, and practice.
Outcome measures Unadjusted and adjusted odds ratios with 95% confidence intervals for myocardial infarction associated with rofecoxib, celecoxib, naproxen, ibuprofen, diclofenac, and other selective and non-selective NSAIDS. Odds ratios were adjusted for smoking status, comorbidity, deprivation, and use of statins, aspirin, and antidepressants.
Results A significantly increased risk of myocardial infarction was associated with current use of rofecoxib (adjusted odds ratio 1.32, 95% confidence interval 1.09 to 1.61) compared with no use within the previous three years; with current use of diclofenac (1.55, 1.39 to 1.72); and with current use of ibuprofen (1.24, 1.11 to 1.39). Increased risks were associated with the other selective NSAIDs, with naproxen, and with non-selective NSAIDs; these risks were significant at < 0.05 rather than < 0.01 for current use but significant at < 0.01 in the tests for trend. No significant interactions occurred between any of the NSAIDs and either aspirin or coronary heart disease.
Conclusion These results suggest an increased risk of myocardial infarction associated with current use of rofecoxib, diclofenac, and ibuprofen despite adjustment for many potential confounders. No evidence was found to support a reduction in risk of myocardial infarction associated with current use of naproxen. This is an observational study and may be subject to residual confounding that cannot be fully corrected for. However, enough concerns may exist to warrant a reconsideration of the cardiovascular safety of all NSAIDs.
Cyclo-oxygenase-2 (COX 2) inhibitors are a selective type of non-steroidal anti-inflammatory drug (NSAID) developed for the treatment of acute inflammation in joints caused by arthritis without the gastrointestinal side effects associated with traditional NSAIDs.1 Although evidence shows that COX 2 inhibitors are as effective as traditional NSAIDs in relieving pain,2 3 serious concerns about their cardiovascular safety have arisen. In the Vioxx gastrointestinal outcomes research (VIGOR) study, patients taking rofecoxib had a much higher risk of myocardial infarction than did patients taking the comparator drug (naproxen). Initially, suggestions were made that the difference was due to a cardioprotective effect of naproxen rather than a deleterious effect of rofecoxib.3 However, this is now known not to be the case, and Merck has very recently ordered an immediate worldwide withdrawal of rofecoxib because of its adverse cardiovascular profile.
Despite this, important questions remain about the safety of other COX 2 inhibitors. The major trials have excluded patients with coronary heart disease,4 and none (with the exception of the recently reported therapeutic arthritis research and gastrointestinal event trial5) has been designed to measure coronary end points. This has left a serious lack of evidence on the safety of COX 2 inhibitors in high risk patients with coronary heart disease,4 6-9 including those on aspirin. This is particularly important given the extent to which COX 2 inhibitors are now being used and that they are still recommended in guidelines for elderly patients.10
We did a population based nested case-control study using the new QRESEARCH database11 to determine the comparative risk of myocardial infarction in patients taking COX 2 inhibitors and other NSAIDs in primary care between 2000 and 2004. We investigated the risk of myocardial infarction associated with these drugs in patients with and without pre-existing coronary heart disease and in those taking and not taking aspirin. Although this analysis was completed before the announcement of the withdrawal of rofecoxib and now valdecoxib, we think it sheds light on the risk profile of other NSAIDs, the use of which is likely to increase following the withdrawal of rofecoxib.
Method
Study population and data source
We used data from UK general practices contributing to the new QRESEARCH database (www.qresearch.org). This is a new clinical database containing the clinical records of more than 7 million patients ever registered with 468 practices over the past 16 years. The information recorded on the database includes demographics (year of birth, sex, socioeconomic data associated with postcode area), characteristics (height, weight, smoking status), symptoms, clinical diagnosis, consultations, referrals, prescribed drugs, and results of investigations. The database has been validated by comparing birth rates, death rates, consultation rates, prevalence, and mortality with other data sources including the general household survey and the general practice research database.12 The age-sex structure of the population has been compared with that reported in the 2001 census. We found a good correspondence for all of these measures (results available on request), although in some instances our prevalence figures were marginally higher than less recent data.13 We have also compared practices taking part in regional research networks on these and other measures and found a good correspondence.14 Detailed analyses have shown good levels of completeness and consistency.15 Similar databases have been used for studies investigating risk factors for coronary heart disease or effects of conventional NSAIDs.16-19 In previous studies, the diagnosis of acute myocardial infarction has been confirmed by reviewing hospital discharge notes or comparison with the paper based records and found to be correct in more than 90% of cases.18-20
The study period ran between 1 August 2000 and 31 July 2004 (the date of the most recent download of QRESEARCH data at the time of the analysis). We used this period as rofecoxib and celecoxib were both available on prescription in the United Kingdom.
Cohort definition
We selected practices that had their current Egton Medical Information Services (EMIS) computer system installed before 1 August 1999. We identified a cohort of patients registered on 1 August 2000 who had been registered for the whole of the preceding 12 months. Patients entered the study period on 1 August 2000 and left the risk period when they developed a myocardial infarction, died, or left the practice or when the study period ended, whichever was earlier.
We identified potential cases of acute myocardial infarction on the basis of a first time diagnosis of acute myocardial infarction recorded with appropriate Read codes during the four year study period. We excluded patients with a myocardial infarction before the start of the study period. We included in the cohort other patients with a diagnosis of coronary heart disease (but without mention of a myocardial infarction). We used this cohort to determine the incidence of myocardial infarction by age and sex.
Case-control analysis
Cases were all patients aged 25 to 100 with a first ever myocardial infarction identified in the cohort analysis. We included patients who had a diagnosis of myocardial infarction recorded as the cause of death. We matched up to 10 controls to each case by age, calendar time, sex, and practice by using incidence density sampling. All controls were alive and registered with the practice at the time their matched case had the myocardial infarction. We derived an index date for each control, which was the date of myocardial infarction of their matched case. We excluded cases and controls who had less than three years of computerised prescribing data available before their index date to ensure that the prescribing data were complete.
Assessment of exposure
We used standardised computerised routines to extract and code data on the medical history and use of prescribed drugs before the index date for each set of cases and controls. We identified all prescriptions for selective and non-selective NSAIDs in the three years before their index date. Twenty seven different NSAIDs were in use during the study period. We grouped the drugs as follows: celecoxib, rofecoxib, ibuprofen, diclofenac (including combination preparations), naproxen, other selective NSAIDS (meloxicam, etoricoxib, etodolac, valdecoxib), and other non-selective NSAIDs. We compared the prescribing rates for each drug per 1000 population with data from the prescribing cost analysis tool (PACT) for 2002 for drugs prescribed by general practice and dispensed in the community and found similar rates and rank order for the preparations.
For each drug group we identified the first and last prescription date and the total number of prescriptions issued in the three years before the index date. We coded the time since last prescription as not prescribed within the past three years, prescribed within 90 days (defined as current use), or prescribed more than 90 days ago. We categorised the total number of prescriptions for each drug group as zero, one to three, and more than three prescriptions. We tested for trend by using the actual number of prescriptions issued within the three year period. General practitioners in the United Kingdom issue patients with sufficient drugs to last one calendar month, so one prescription is approximately equivalent to one month of treatment.
Statistical analysis
We used conditional logistic regression for individually matched case-control studies to derive odds ratios with 95% confidence intervals for myocardial infarction associated with each of our drug groups. We made adjustments for possible confounding effects of smoking (smoker, not smoker, not recorded), comorbidity (diabetes, hypertension, coronary heart disease, osteoarthritis, rheumatoid arthritis, obesity), and deprivation in fifths. We used the Townsend score based on the 2001 census related data associated with the output area of each patient's postcode as a measure of deprivation.21 We categorised obesity as body mass index (kg/m2) less than 30, 30 or more, or not recorded. We also adjusted for the use of other drugs known to affect the risk of myocardial infarction or to be commonly associated with use of NSAIDS—namely, antidepressants16 (selective serotonin uptake inhibitors and tricyclic antidepressants separately) and statins.22 We also adjusted the results for each drug group for the other NSAID groups.
We calculated the numbers needed to harm by applying the incidence of first myocardial infarction per 1000 using the adjusted odds ratio from current usage of drugs. We calculated this separately for all patients aged 25 and over and for those aged 65 and over. We calculated approximate 95% confidence intervals. We examined two way interactions between different NSAIDs and aspirin and coronary heart disease. We fitted a second model restricted to cases and controls with complete data for smoking status and body mass index. We fitted a third model restricted to patients without either coronary heart disease or diabetes in order to reduce possible effects of residual confounding.23 We used Stata (version 8.2) for all the analyses. We selected a P value of 0.01 (two tailed) as significant.
Results
We used the fourth version of the QRESEARCH database for this analysis. We identified 9218 cases with a first ever myocardial infarction between the ages of 25 and 100 (63.1% men). We matched these by age, calendar time, sex, and practice to 86 349 controls, which gave an average of 9.4 controls for each case. The median number of months of prior data available was 86 (interquartile range 63-117). The crude incidence of myocardial infarction was 1.71 per 1000 person years for patients aged 25 years and over, rising to 4.57 per 1000 person years for patients aged 65 years and over.
Table 1 shows the baseline characteristics of cases and their controls. Cases and controls were well matched for age, sex, and the number of months of previous data available for analysis. As expected, a higher proportion of cases were smokers, were obese, and had comorbidities. Cases also tended to be from slightly more deprived areas than controls.
Table 1 Characteristics of cases and matched controls. Values are numbers (percentages) unless stated otherwise
Table 2 shows the pattern of use of the different drug groups in cases and controls. Table 3 shows the unadjusted and adjusted odds ratios for myocardial infarction associated with current use of each type of NSAID. The unadjusted analysis showed that each drug group was associated with a significantly increased risk of myocardial infarction. In the multivariate analysis, we adjusted for potential confounders (smoking status, diabetes, hypertension, coronary heart disease, osteoarthritis, rheumatoid arthritis, obesity, deprivation (fifth of Townsend score), and use of selective serotonin uptake inhibitors, tricyclic antidepressants, statins, and aspirin). Table 3 shows that the use of rofecoxib within the previous three months was associated with a significantly increased risk of myocardial infarction (adjusted odds ratio 1.32, 95% confidence interval 1.09 to 1.61), as was use of ibuprofen (1.24, 1.11 to 1.39) and diclofenac (1.55, 1.39 to 1.72).
Table 2 Cases and controls with prescriptions for non-steroidal anti-inflammatory drugs (NSAIDs) within previous three years. Values are numbers (percentages)
Table 3 Odds ratios for use of non-steroidal anti-inflammatory drugs (NSAIDs) within previous three years for cases and controls
Use of other selective NSAIDs within the previous three months was also associated with a significantly increased risk of myocardial infarction in the unadjusted analysis (unadjusted odds ratio 1.55, 1.25 to 1.92). The magnitude of the odds ratio was reduced after adjustment for potential confounders (adjusted odds ratio 1.27, 1.00 to 1.61). Similarly, we found a tendency to increased risks for use of naproxen and other non-selective NSAIDs within the previous three months, as shown in table 3. The numbers needed to harm for use of each drug within the previous three months for patients aged 65 years and over were 521 (95% confidence interval 355 to 866) for diclofenac, 1005 (569 to 3089) for ibuprofen, and 695 (344 to 3841) for rofecoxib. For patients aged 25 and over the numbers needed to harm were 2444 (1504 to 5332) for ibuprofen, 1066 (815 to 1504) for diclofenac, and 1833 (961 to 6517) for rofecoxib.
Table 3 also shows the adjusted odds ratios for patients whose last prescription was more than three months before the index date. Apart from one category of drugs (the other selective NSAIDs), the odds ratios were all above one and ranged from 1.05 to 1.18.
We repeated the analyses, restricting them to cases and controls with complete data for smoking and body mass index and obtained similar odds ratios for all the drugs except for naproxen, for which the adjusted odds ratio for use within the previous three months was 1.42 (1.09 to 1.85), and the group of other non-selective NSAIDs, for which the adjusted odds ratio for use within the previous three months was 1.11 (0.90 to 1.37). We also restricted the analysis to patients aged 65 and over; the odds ratios were similar for all the drugs except the group of other non-selective NSAIDs, for which the adjusted odds ratio for use within the previous three months was 1.14 (0.93 to 1.24)
We repeated the analysis again, restricting it to patients without either coronary heart disease or diabetes. This did not affect the odds ratios substantially, apart from use of celecoxib within the previous three months (adjusted odds ratio 1.02, 0.74 to 1.39).
We examined the odds ratios for myocardial infarction associated with increasing numbers of prescriptions for each of the drugs. We found highly significant tests for trend, with increased risk of myocardial infarction associated with increasing number of prescriptions for diclofenac, ibuprofen, naproxen, and other NSAIDs. The adjusted odds ratio for more than three prescriptions compared with no prescriptions were 1.46 (1.33 to 1.60) for diclofenac, 1.14 (1.03 to 1.27) for ibuprofen, 1.27 (1.06 to 1.53) for naproxen, and 1.28 (1.12 to 1.47) for other non-selective NSAIDs. We found no clear pattern for rofecoxib (test for trend = 0.13).
We found no significant interactions between any NSAID and aspirin, indicating that the risk of myocardial infarction for each NSAID does not vary according to whether aspirin is prescribed. Similarly, we found no significant interactions between any NSAID and coronary heart disease, although the odds ratios tended to be higher in patients without pre-existing coronary heart disease.
Discussion
Blower A, Brooks A, Fenn G, Hill A, Perarce M, Morant SV. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997;11: 283-91.
Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib vs. non-steroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. JAMA 2000;284: 1247-55.
Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343: 1520-8.
Topol E, Falk G. A coxib a day won't keep the doctor away. Lancet 2004;364: 640-1.
Farkouh ME, Kishner H, Harrington RA, Ruland S, Verheught FW, Schnitzer TJ, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 2004;364: 675-84.
Juni P, Rutjes AWS, Dieppe P. Are selective COX 2 inhibitors superior to traditional non-steroidal anti-inflammatory drugs? BMJ 2002;324: 1287-8.
Wright JM. The double-edged sword of COX-2 selective NSAIDs. CMAJ 2002;167: 1131-7.
Jones R. Efficacy and safety of COX 2 inhibitors. BMJ 2002;325: 607-8.
Dieppe P, Bartlett C, Davey P, Doyal L, Ebrahim S. Balancing benefits and harms: the example of non-steroidal anti-inflammatory drugs. BMJ 2004;329: 31-4.
National Institute for Clinical Excellence. Guidance on the use of cyclo-oxygenase (Cox) II selective inhibitors, celecoxib, rofecoxib, meloxicam and etodolac for osteoarthritis and rheumatoid arthritis. London: NICE, 2001. (Technology appraisal guidance No 27.)
Hippisley-Cox J, Stables D, Pringle M. QRESEARCH—a new general practice database for research. Journal of Informatics in Primary Care 2004;12: 49-50.
Office of National Statistics. Key health statistics from general practice. London: Department of Health, 1998: 192.
Hippisley-Cox J, Pringle M. Prevalence, care and outcomes for patients with diet controlled diabetes in general practice: cross sectional survey. Lancet 2004;364: 423-5.
Hammersley V, Hippisley-Cox J, Wilson A, Pringle M. A comparison of research general practices and their patients with other practices—cross sectional survey in Trent. Br J Gen Pract 2002;52: 463-8.
Hippisley-Cox J, Hammersley V, Pringle M, Coupland C, Crown N, Wright L. How useful are general practice databases for research? Analysis of their accuracy and completeness in one research network. Health Informatics Journal 2004;10: 91-109.
Hippisley-Cox J, Pringle M, Hammersley V, Crown N, Meal A, Wynn A. Antidepressants as a risk factor for ischaemic heart disease: case control study in general practice. BMJ 2001;323: 666-9.
Schlienger R, Jick H, Meier CR. Use of non steroidal anti-inflammatory drugs and risk of first time acute myocardial infarction. Br J Clin Pharmacol 2002;54: 327-32.
Jick H, Vasilakis C, Derby LE. Antihypertensive drugs and fatal myocardial infarction in persons with uncomplicated hypertension. Epidemiology 1997;8: 446-8.
Meier CR, Jick SS, Derby LE, Vasilakis C, Jick H. Acute respiratory infections and risk of first time acute myocardial infarction. Lancet 1998;351: 1467-71.
Hippisley-Cox J, Pringle M. Depression and risk of ischaemic heart disease in men: authors' reply. BMJ 1998;317: 1450.
Townsend P. Deprivation. J Soc Policy 1987;16: 125-46.
Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S). Lancet 1994;344: 1383-9.
McMahan AD. Approaches to combat with confounding by indication in observational studies of intended drug effects. Pharmacoepidemiol Drug Saf 2003;12: 551-8.
Ray W, Stein M, Hall K, Daugherty J, Griffin M. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: observational cohort study. Lancet 2002;359: 118-23.
Juni P, Nartey L, Reichenback S, Sterchi R, Dieppe P, Matthias E. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004;364: 2021-9.
Soloman D, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med 2002;162: 1099-104.
Watson DJ, Rhodes T, Cai B, Guess HA. Lower risk of thromboembolic events with naproxen among patients with rheumatoid arthritis. Arch Intern Med 2002;162: 1105-10.
Mamdani M, Rochon P, Juurlink DN, Anderson GM, Kopp A, Naglie G, et al. Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Arch Intern Med 2003;163: 481-6.
Vandenbroucke J. Benefits and harms of drug treatments. BMJ 2004;329: 2-3.
MacDonald TM, Morant SV, Goldstein JL, Burke TA, Pettitt D. Channelling bias and the incidence of gastrointestinal haemorrhage in users of meloxicam, coxibs, and older, non-specific non-steroidal anti-inflammatory drugs. Gut 2003;52: 1265-70.
Department of Health. National service framework for coronary artery disease: modern standards and service models. London: Stationery Office, 2000.
Rothman K, Greenland S. Modern epidemiology. 2nd ed. Boston: Lippincott-Raven, 1998.(Julia Hippisley-Cox, professor of clinic)
Correspondence to: J Hippisley-Cox Julia.hippisley-cox@nottingham.ac.uk
Aims To determine the comparative risk of myocardial infarction in patients taking cyclo-oxygenase-2 and other non-steroidal anti-inflammatory drugs (NSAIDs) in primary care between 2000 and 2004; to determine these risks in patients with and without pre-existing coronary heart disease and in those taking and not taking aspirin.
Design Nested case-control study.
Setting 367 general practices contributing to the UK QRESEARCH database and spread throughout every strategic health authority and health board in England, Wales, and Scotland.
Subjects 9218 cases with a first ever diagnosis of myocardial infarction during the four year study period; 86 349 controls matched for age, calendar year, sex, and practice.
Outcome measures Unadjusted and adjusted odds ratios with 95% confidence intervals for myocardial infarction associated with rofecoxib, celecoxib, naproxen, ibuprofen, diclofenac, and other selective and non-selective NSAIDS. Odds ratios were adjusted for smoking status, comorbidity, deprivation, and use of statins, aspirin, and antidepressants.
Results A significantly increased risk of myocardial infarction was associated with current use of rofecoxib (adjusted odds ratio 1.32, 95% confidence interval 1.09 to 1.61) compared with no use within the previous three years; with current use of diclofenac (1.55, 1.39 to 1.72); and with current use of ibuprofen (1.24, 1.11 to 1.39). Increased risks were associated with the other selective NSAIDs, with naproxen, and with non-selective NSAIDs; these risks were significant at < 0.05 rather than < 0.01 for current use but significant at < 0.01 in the tests for trend. No significant interactions occurred between any of the NSAIDs and either aspirin or coronary heart disease.
Conclusion These results suggest an increased risk of myocardial infarction associated with current use of rofecoxib, diclofenac, and ibuprofen despite adjustment for many potential confounders. No evidence was found to support a reduction in risk of myocardial infarction associated with current use of naproxen. This is an observational study and may be subject to residual confounding that cannot be fully corrected for. However, enough concerns may exist to warrant a reconsideration of the cardiovascular safety of all NSAIDs.
Cyclo-oxygenase-2 (COX 2) inhibitors are a selective type of non-steroidal anti-inflammatory drug (NSAID) developed for the treatment of acute inflammation in joints caused by arthritis without the gastrointestinal side effects associated with traditional NSAIDs.1 Although evidence shows that COX 2 inhibitors are as effective as traditional NSAIDs in relieving pain,2 3 serious concerns about their cardiovascular safety have arisen. In the Vioxx gastrointestinal outcomes research (VIGOR) study, patients taking rofecoxib had a much higher risk of myocardial infarction than did patients taking the comparator drug (naproxen). Initially, suggestions were made that the difference was due to a cardioprotective effect of naproxen rather than a deleterious effect of rofecoxib.3 However, this is now known not to be the case, and Merck has very recently ordered an immediate worldwide withdrawal of rofecoxib because of its adverse cardiovascular profile.
Despite this, important questions remain about the safety of other COX 2 inhibitors. The major trials have excluded patients with coronary heart disease,4 and none (with the exception of the recently reported therapeutic arthritis research and gastrointestinal event trial5) has been designed to measure coronary end points. This has left a serious lack of evidence on the safety of COX 2 inhibitors in high risk patients with coronary heart disease,4 6-9 including those on aspirin. This is particularly important given the extent to which COX 2 inhibitors are now being used and that they are still recommended in guidelines for elderly patients.10
We did a population based nested case-control study using the new QRESEARCH database11 to determine the comparative risk of myocardial infarction in patients taking COX 2 inhibitors and other NSAIDs in primary care between 2000 and 2004. We investigated the risk of myocardial infarction associated with these drugs in patients with and without pre-existing coronary heart disease and in those taking and not taking aspirin. Although this analysis was completed before the announcement of the withdrawal of rofecoxib and now valdecoxib, we think it sheds light on the risk profile of other NSAIDs, the use of which is likely to increase following the withdrawal of rofecoxib.
Method
Study population and data source
We used data from UK general practices contributing to the new QRESEARCH database (www.qresearch.org). This is a new clinical database containing the clinical records of more than 7 million patients ever registered with 468 practices over the past 16 years. The information recorded on the database includes demographics (year of birth, sex, socioeconomic data associated with postcode area), characteristics (height, weight, smoking status), symptoms, clinical diagnosis, consultations, referrals, prescribed drugs, and results of investigations. The database has been validated by comparing birth rates, death rates, consultation rates, prevalence, and mortality with other data sources including the general household survey and the general practice research database.12 The age-sex structure of the population has been compared with that reported in the 2001 census. We found a good correspondence for all of these measures (results available on request), although in some instances our prevalence figures were marginally higher than less recent data.13 We have also compared practices taking part in regional research networks on these and other measures and found a good correspondence.14 Detailed analyses have shown good levels of completeness and consistency.15 Similar databases have been used for studies investigating risk factors for coronary heart disease or effects of conventional NSAIDs.16-19 In previous studies, the diagnosis of acute myocardial infarction has been confirmed by reviewing hospital discharge notes or comparison with the paper based records and found to be correct in more than 90% of cases.18-20
The study period ran between 1 August 2000 and 31 July 2004 (the date of the most recent download of QRESEARCH data at the time of the analysis). We used this period as rofecoxib and celecoxib were both available on prescription in the United Kingdom.
Cohort definition
We selected practices that had their current Egton Medical Information Services (EMIS) computer system installed before 1 August 1999. We identified a cohort of patients registered on 1 August 2000 who had been registered for the whole of the preceding 12 months. Patients entered the study period on 1 August 2000 and left the risk period when they developed a myocardial infarction, died, or left the practice or when the study period ended, whichever was earlier.
We identified potential cases of acute myocardial infarction on the basis of a first time diagnosis of acute myocardial infarction recorded with appropriate Read codes during the four year study period. We excluded patients with a myocardial infarction before the start of the study period. We included in the cohort other patients with a diagnosis of coronary heart disease (but without mention of a myocardial infarction). We used this cohort to determine the incidence of myocardial infarction by age and sex.
Case-control analysis
Cases were all patients aged 25 to 100 with a first ever myocardial infarction identified in the cohort analysis. We included patients who had a diagnosis of myocardial infarction recorded as the cause of death. We matched up to 10 controls to each case by age, calendar time, sex, and practice by using incidence density sampling. All controls were alive and registered with the practice at the time their matched case had the myocardial infarction. We derived an index date for each control, which was the date of myocardial infarction of their matched case. We excluded cases and controls who had less than three years of computerised prescribing data available before their index date to ensure that the prescribing data were complete.
Assessment of exposure
We used standardised computerised routines to extract and code data on the medical history and use of prescribed drugs before the index date for each set of cases and controls. We identified all prescriptions for selective and non-selective NSAIDs in the three years before their index date. Twenty seven different NSAIDs were in use during the study period. We grouped the drugs as follows: celecoxib, rofecoxib, ibuprofen, diclofenac (including combination preparations), naproxen, other selective NSAIDS (meloxicam, etoricoxib, etodolac, valdecoxib), and other non-selective NSAIDs. We compared the prescribing rates for each drug per 1000 population with data from the prescribing cost analysis tool (PACT) for 2002 for drugs prescribed by general practice and dispensed in the community and found similar rates and rank order for the preparations.
For each drug group we identified the first and last prescription date and the total number of prescriptions issued in the three years before the index date. We coded the time since last prescription as not prescribed within the past three years, prescribed within 90 days (defined as current use), or prescribed more than 90 days ago. We categorised the total number of prescriptions for each drug group as zero, one to three, and more than three prescriptions. We tested for trend by using the actual number of prescriptions issued within the three year period. General practitioners in the United Kingdom issue patients with sufficient drugs to last one calendar month, so one prescription is approximately equivalent to one month of treatment.
Statistical analysis
We used conditional logistic regression for individually matched case-control studies to derive odds ratios with 95% confidence intervals for myocardial infarction associated with each of our drug groups. We made adjustments for possible confounding effects of smoking (smoker, not smoker, not recorded), comorbidity (diabetes, hypertension, coronary heart disease, osteoarthritis, rheumatoid arthritis, obesity), and deprivation in fifths. We used the Townsend score based on the 2001 census related data associated with the output area of each patient's postcode as a measure of deprivation.21 We categorised obesity as body mass index (kg/m2) less than 30, 30 or more, or not recorded. We also adjusted for the use of other drugs known to affect the risk of myocardial infarction or to be commonly associated with use of NSAIDS—namely, antidepressants16 (selective serotonin uptake inhibitors and tricyclic antidepressants separately) and statins.22 We also adjusted the results for each drug group for the other NSAID groups.
We calculated the numbers needed to harm by applying the incidence of first myocardial infarction per 1000 using the adjusted odds ratio from current usage of drugs. We calculated this separately for all patients aged 25 and over and for those aged 65 and over. We calculated approximate 95% confidence intervals. We examined two way interactions between different NSAIDs and aspirin and coronary heart disease. We fitted a second model restricted to cases and controls with complete data for smoking status and body mass index. We fitted a third model restricted to patients without either coronary heart disease or diabetes in order to reduce possible effects of residual confounding.23 We used Stata (version 8.2) for all the analyses. We selected a P value of 0.01 (two tailed) as significant.
Results
We used the fourth version of the QRESEARCH database for this analysis. We identified 9218 cases with a first ever myocardial infarction between the ages of 25 and 100 (63.1% men). We matched these by age, calendar time, sex, and practice to 86 349 controls, which gave an average of 9.4 controls for each case. The median number of months of prior data available was 86 (interquartile range 63-117). The crude incidence of myocardial infarction was 1.71 per 1000 person years for patients aged 25 years and over, rising to 4.57 per 1000 person years for patients aged 65 years and over.
Table 1 shows the baseline characteristics of cases and their controls. Cases and controls were well matched for age, sex, and the number of months of previous data available for analysis. As expected, a higher proportion of cases were smokers, were obese, and had comorbidities. Cases also tended to be from slightly more deprived areas than controls.
Table 1 Characteristics of cases and matched controls. Values are numbers (percentages) unless stated otherwise
Table 2 shows the pattern of use of the different drug groups in cases and controls. Table 3 shows the unadjusted and adjusted odds ratios for myocardial infarction associated with current use of each type of NSAID. The unadjusted analysis showed that each drug group was associated with a significantly increased risk of myocardial infarction. In the multivariate analysis, we adjusted for potential confounders (smoking status, diabetes, hypertension, coronary heart disease, osteoarthritis, rheumatoid arthritis, obesity, deprivation (fifth of Townsend score), and use of selective serotonin uptake inhibitors, tricyclic antidepressants, statins, and aspirin). Table 3 shows that the use of rofecoxib within the previous three months was associated with a significantly increased risk of myocardial infarction (adjusted odds ratio 1.32, 95% confidence interval 1.09 to 1.61), as was use of ibuprofen (1.24, 1.11 to 1.39) and diclofenac (1.55, 1.39 to 1.72).
Table 2 Cases and controls with prescriptions for non-steroidal anti-inflammatory drugs (NSAIDs) within previous three years. Values are numbers (percentages)
Table 3 Odds ratios for use of non-steroidal anti-inflammatory drugs (NSAIDs) within previous three years for cases and controls
Use of other selective NSAIDs within the previous three months was also associated with a significantly increased risk of myocardial infarction in the unadjusted analysis (unadjusted odds ratio 1.55, 1.25 to 1.92). The magnitude of the odds ratio was reduced after adjustment for potential confounders (adjusted odds ratio 1.27, 1.00 to 1.61). Similarly, we found a tendency to increased risks for use of naproxen and other non-selective NSAIDs within the previous three months, as shown in table 3. The numbers needed to harm for use of each drug within the previous three months for patients aged 65 years and over were 521 (95% confidence interval 355 to 866) for diclofenac, 1005 (569 to 3089) for ibuprofen, and 695 (344 to 3841) for rofecoxib. For patients aged 25 and over the numbers needed to harm were 2444 (1504 to 5332) for ibuprofen, 1066 (815 to 1504) for diclofenac, and 1833 (961 to 6517) for rofecoxib.
Table 3 also shows the adjusted odds ratios for patients whose last prescription was more than three months before the index date. Apart from one category of drugs (the other selective NSAIDs), the odds ratios were all above one and ranged from 1.05 to 1.18.
We repeated the analyses, restricting them to cases and controls with complete data for smoking and body mass index and obtained similar odds ratios for all the drugs except for naproxen, for which the adjusted odds ratio for use within the previous three months was 1.42 (1.09 to 1.85), and the group of other non-selective NSAIDs, for which the adjusted odds ratio for use within the previous three months was 1.11 (0.90 to 1.37). We also restricted the analysis to patients aged 65 and over; the odds ratios were similar for all the drugs except the group of other non-selective NSAIDs, for which the adjusted odds ratio for use within the previous three months was 1.14 (0.93 to 1.24)
We repeated the analysis again, restricting it to patients without either coronary heart disease or diabetes. This did not affect the odds ratios substantially, apart from use of celecoxib within the previous three months (adjusted odds ratio 1.02, 0.74 to 1.39).
We examined the odds ratios for myocardial infarction associated with increasing numbers of prescriptions for each of the drugs. We found highly significant tests for trend, with increased risk of myocardial infarction associated with increasing number of prescriptions for diclofenac, ibuprofen, naproxen, and other NSAIDs. The adjusted odds ratio for more than three prescriptions compared with no prescriptions were 1.46 (1.33 to 1.60) for diclofenac, 1.14 (1.03 to 1.27) for ibuprofen, 1.27 (1.06 to 1.53) for naproxen, and 1.28 (1.12 to 1.47) for other non-selective NSAIDs. We found no clear pattern for rofecoxib (test for trend = 0.13).
We found no significant interactions between any NSAID and aspirin, indicating that the risk of myocardial infarction for each NSAID does not vary according to whether aspirin is prescribed. Similarly, we found no significant interactions between any NSAID and coronary heart disease, although the odds ratios tended to be higher in patients without pre-existing coronary heart disease.
Discussion
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