Risk of myocardial infarction on Cox 2 & conventional NSAIDs

1. Risk of myocardial infarction on Cox 2 & conventional NSAIDs Julia Hippisley-Cox Carol Coupland

2. Goals of presentation • Overall • Present analysis of study examining risk of MI in patients on NSAIDS • Initially • Overview of data source (QRESEARCH) used for the project to set context

3. Acknowledgements • Co-author • Carol Coupland • QRESEARCH team • Mike Pringle • Mike Heaps • Justin Fenty • Gavin Langford • David Stables • EMIS and EMIS practices

4. QRESEARCH:What is it? • Patient level consolidated database • Anonmyised data • Longitudinal data for 15+ years • Derived from GP clinical records • Validated against external and internal measures • Industry independent

5. QRESEARCH:UK coverage • Largest database in the world • 488 UK practices • > 6 practices in every Strategic Health Authority (administrative area) • > 8 million patients including those who died, left and still registered • > 29 million person years observation

6. QRESEARCH:Data contents • Socio-demographics • Diagnoses • Clinical values • Laboratory tests • Prescription data • Consultation data • Category of clinician entering data

7. Study aims • To determine risk of Myocardial Infarction in patients taking • use Cox 2 inhibitors • traditional NSAIDS • Compared with non use

8. Background • Cox 2 drugs • Type of painkiller • Supposed to cause less gastrointestinal problems than traditional NSAIDS • But original RCT compared rofecoxib with naproxen • Found 5 fold increased risk of MI • Adverse effect of Rofecoxib • Beneficial effect of naproxen

9. Study design & setting • Nested case control study • 367 UK practices contributing to the new UK QRESEARCH • Registered population > 3 million patients [6% UK population] • Study period Aug 2000-July 2004

10. Study cohort • All patients aged 25-100 • Registered with practices from 1st Aug 2000 to 31st July 2004 • Prior registration >12 months • > 8 million person years observation • 9218 patients with a first MI

12. Case & controls • CASES • 1st ever MI during 4 year study period • CONTROLS • 10 controls matched by • age • Sex • Practice • Calendar year • Cases & controls all with 3 years + prior data

13. Exposure • Main exposure • Use of any NSAID in 3 years prior to index date • Extracted • Type • Date • Count of prescription

14. Types of NSAIDS • Overall 27 various NSAIDS • Groups for analysis • Celecoxib • Rofecoxib • Other Cox2 • Diclofenac • Ibuprofen • Naproxen • Other NSAIDs

15. Confounders • Ischaemic heart disease • Diabetes • Hypertension • OA • Rheumatoid arthritis • Smoking • Obesity • Deprivation • Aspirin • Statins • Antidepressants

16. Statistical analysis • Conditional logistic regression • Odds ratios + 95% CI • Unadjusted & adjusted • Investigations for interactions

17. Results: baseline • Cases & controls well matched for • Age, sex, time, practice • Cases had higher prevalence • Smoking • Obesity • Deprivation • comorbidity

18. Increased risk of MI (95% CI) • Increased risk of MI current use of • Rofecoxib 30% increase (10%-60%) • Other Cox 2 27% increase (0%-60%) • Diclofenac 55% increase (40%-70%) • Ibuprofen 20% increase (10%-40%) • V significant duration response • More scripts causing higher risk

19. Numbers needed to harm (aged 25 plus) • No. patients treated for one year for one additional MI to result • Diclofenac 1066 (95% CI 815 -1504) • Rofecoxib 1833 (955% CI 961-6517) • ibuprofen 2444 (95% CI 1504-5332)

20. Numbers needed to harm(patients 65 plus) • No. patients 65 + treated for one year for one additional MI to result • Diclofenac 521 (95% CI 355 to 866) • Rofecoxib 695 (95% CI 344 to 3841) • Ibuprofen 1005 (95% CI 569 to 3089)

21. Interactions, age, naproxen • No convincing interactions • Aspirin & NSAIDS • CHD and any NSAID • So risk applies despite presence of these • No evidence that Naproxen lowers risk MI

22. Limitations study • Observational study • Subject to bias • Misclassification • Recording bias • Confounding by indication • But likely to have applied to all NSAIDS • Residual confounding

23. Overcoming confoundingby indication • To address confounding by indication restricted analysis to those without • Diabetes • Ischaemic heart disease • Also restricted analysis aged > 65 years • This did not change results

24. Setting it in context • Since this work was completed • Rofecoxib withdrawn • Valdecoxib withdrawn • Celecoxib risk • FDA memo on web • Suggests class effect not just Cox 2 but also NSAIDs but serious lack of placebo controlled safety data

25. However • Observational studies cannot prove anything • They are subject to residual confounding • They can only raise concerns • Sometimes observational studies are wrong eg HRT • Rapid access to very large representative samples & potential • Can help evaluate risks & benefits outside RCT setting

26. Conclusions • Our study suggests risk of MI is a class effect as conventional NSAIDs also seem to increase risk • FDA memo also suggests this • ? Time to evaluate cardiovascular safety all NSAIDs