Research Article: Statins and Risk of Lower Limb Revision Surgery: The Influence of Differences in Study Design Using Electronic Health Records From the United Kingdom and Denmark

Date Published: July 01, 2016

Publisher: Oxford University Press

Author(s): Arief Lalmohamed, Tjeerd P. van Staa, Peter Vestergaard, Hubertus G. M. Leufkens, Anthonius de Boer, Pieter Emans, Cyrus Cooper, Frank de Vries.


Previous observational studies on statins have shown variable results based on the methodology used. Our objective was to study the association between statins and orthopedic implant failure and to explore the influence of methodological differences in study design. Our study base consisted of patients with a primary total joint replacement in Denmark and the United Kingdom (n = 189,286; 1987–2012). We used 4 study designs: 1) case-control (each patient with revision surgery matched to 4 controls), 2) time-dependent cohort (postoperative statin use as a time-varying exposure variable), 3) immortal time cohort (misclassifying the time postoperatively before statin use), and 4) time-exclusion cohort (excluding the time postoperatively before statin use). Cox proportional hazards models and logistic regression were used to estimate incidence rate ratios. In the time-dependent cohort design, statin use was associated with a decreased risk of revision surgery (adjusted incidence rate ratio (IRR) = 0.90, 95% confidence interval (CI): 0.85, 0.96), which was similar to our case-control results (IRR = 0.87, 95% CI: 0.81, 0.93). In contrast, both time-fixed cohort designs yielded substantially lower risk estimates (IRR = 0.36 (95% CI: 0.34, 0.38) and IRR = 0.65 (95% CI: 0.63, 0.68), respectively). We discourage the use of time-fixed cohort studies, which may falsely suggest protective effects. The simple choice of how to classify exposure can substantially change results from biologically plausible to implausible.

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We identified 119,182 British patients and 70,104 Danish patients who underwent primary TJR surgery (Table 1). Among these patients, 41.3% (n = 49,265) were classified as postoperative statin users in the British cohort, and 24.5% (n = 17,168) were classified as postoperative statin users in the Danish cohort. Baseline characteristics were very similar in the 2 data sources. Overall, statin users and nonusers had a similar mean age (approximately 70 years in British participants and approximately 68 years in Danish participants), and a higher proportion of statin users were males. We had a longer follow-up period in the British cohort (6.1 years for statin users and 5.2 years for nonusers) than in the Danish cohort (4.4 years for statin users and 3.9 years for nonusers). In both cohorts, statin users were more likely to have used glucose-lowering drugs and thiazide diuretics and more often had a history of ischemic heart disease, cerebrovascular disease, or hyperlipidemia. Among persons included in the cohorts, 3,517 British participants and 3,747 Danish participants underwent revision surgery. They were included in the case-control design and matched to 14,068 British and 14,988 Danish control subjects who did not undergo revision surgery.
Table 1.Baseline Characteristics of Statin Users and Nonusers, United Kingdom and Denmark, 1987–2012CharacteristicUnited Kingdom (CPRD)Denmark (DNHS)Statin Use (n = 49,265),Mean (SD)Nonuse (n = 69,917),Mean (SD)Statin Use (n = 17,168),Mean (SD)Nonuse (n = 52,936),Mean (SD)%%%%Follow-up, years6.1 (4.1)5.2 (4.0)4.4 (2.7)3.9 (2.7)Age at index date, years70.2 (8.5)69.5 (10.9)68.2 (8.5)68.3 (10.6)Female sex53.863.455.859.4Body mass indexa,b29.2 (5.1)27.9 (5.3)Smoking statusc Never smoker54.361.7 Current smoker11.911.7 Former smoker33.724.2Alcohol used No21.419.2 Yes74.970.3Medication use within 6 months before index date Calcium or vitamin D6. Oral corticosteroids4. Noninsulin antidiabetics12. Thiazide diuretics28.318.822.917.5 Paracetamol or acetaminophen62.556.433.830.4 NSAIDs52.052.662.061.6 Opioids (tramadol or stronger)37.134.829.428.4 Bisphosphonates4. β blockers25.410.723.811.1 Antiplatelet drugs37.711.235.413.3 Anxiolytics or hypnotics10.210.124.322.6 Proton pump inhibitors27.520.813.610.4Disease history before index date Fracture20.720.521.624.0 Osteoarthritis76.472.097.897.4 Rheumatoid arthritis4. Chronic kidney disease8. Heart failure4. Ischemic heart disease24.95.723.86.3 Cerebrovascular disease9. Hyperlipidemia24.04.511.60.8 Atrial fibrillation5. Hypertension57.734.621.69.8 Type 2 diabetes mellitus15.52.510.62.2 COPD4. Asthma12.411.42.62.4Abbreviations: COPD, chronic obstructive pulmonary disease; CPRD, Clinical Practice Research Datalink; DNHS, Danish National Health System; NSAID, nonsteroidal antiinflammatory drug; SD, standard deviation.a Missing proportions in the CPRD: statin users, 2.7%; nonusers, 10.5%.b Calculated as weight (kg)/height (m)2.c Missing proportions in the CPRD: statin users, 0.1%; nonusers, 2.4%.d Missing proportions in the CPRD: statin users, 3.6%; nonusers, 10.5%.

This study shows that there is probably no causal relationship between statins and implant failure in patients with a replaced hip or knee. Both the case-control design (IRR = 0.87) and the time-dependent cohort design (IRR = 0.90) revealed a slight reduction in implant failure rates. However, the risk did not decrease with a longer duration of statin use. The time-fixed cohort analyses led to substantially lower risk estimates; this observation held for both time-fixed cohort designs but was greater when immortal time was misclassified (IRR = 0.36) than when it was excluded (IRR = 0.65). Differences in confounder-handling techniques or data sources did not substantially alter the study findings.




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