Does co-prescription of statin drugs and its contraindications increase the risk of liver injury? The self-controlled case series approach Henry. K. O. Athiany JKUAT, STACS Department Statistical Modelling Workshop Strathmore University 23rd -27th July, 2012 Presentation outline Background/Intro Literature review (Systematic) Aims and Objectives THIN Database The case-series design Case-series approach Results, findings, summary Results in context: Implications Background/Introduction Cardiovascular disease (CVD) Statin drugs (…most widely prescribed in the UK) Atorvastatin(lipitor), Fluvastatin(lescol), Cerivastatin(lipobay), Pravastatin(pravachol), Rosuvastatin(crestor), Simvastatin(zocor) Statin drug metabolism Cytochrome P450 3A4 (CYP3A4) Statin Contraindicated CYP3A4 Inhibitor Drugs (SCCID)- (short-term: indication for use) azole antifungals: fluconazole, ketoconazole, … macrolide antibiotics: clarithromycin, telithromycin,… Immunosuppressant : cyclosporine Drug Induced Liver Injury (DILI) Literature reviews (LRs) Three part systematic reviews on risk of liver injury in: Chronic statin drug users SCCID users Concomitant statin drug and SCCID users Why three LRs? LR(1): Findings & summary Chronic statin drug use (1987-2011): results indicate; Four (4) studies identified Strong evidence that statin exposure is associated with higher risk of liver injury compared to non-exposure to statin drugs. (esp. 1st one year of statin drug therapy) Evidence of carry-over effects of statin drugs on risk of liver injury (rtn to normal 1yr later) Exposure to high dose statin may be assoc with higher risk of liver injury than low dose statin drug exposure Aim: Present the evidence on the association between statin drug use and the risk of liver injury. Despite the limitations listed ….the following were the findings of the review on the relationship between statin drugs exposure and the risk of liver injury in the period 1987-2011. LR(2): Findings & summary SCCID users (1987-2011): Five (5) studies identified Review supports the hypothesis that exposure to SCCID (macrolides antibiotics-erythromycin, clarithromycin, telithromycin; fluconazole) is associated with higher risk of liver injury compared to non-exposure (baseline) to these drugs. Potential confounders identified: gender, age, ethnicity, cigarette smoking, co-morbidities, diabetes, e.t.c More research to clarify on the relationship between SCCID and the risk of liver injury. Aim: Present the evidence on the association between SCCID use and the risk of liver injury. LR(3): Findings & summary Concomitant statin drug and SCCID use No studies identified First study to review the literature on the association between risk of liver injury and exposure to co-prescription of statin drugs and SCCID among adult chronic statin users. Results supports the need to carry out a population based study, to assess this association among adult patients on long-term statin therapy. Aim: Present the evidence on the association between co-prescription of statin drug and SCCID and the risk of liver injury. To my knowledge, this appears to be the ……….. Results of this review was a motivation of the current study on the risk of liver given co-prescription of statin drugs and SCCID to chromic statin users. LR: Overall summary Exposure to statin drugs or SCCID is associated with higher risk of liver injury than non-exposure to these drugs. There is limited/no evidence of research (1987-2011) that has considered assessing the association between co-prescription, and eventually concomitant exposure to both statin drugs and SCCID, and the risk on liver injury. In summary I can say that…….. SCCID(macrolides antibiotics-erythromycin, clarithromycin, telithromycin; fluconazole) Aim To asses the association between co-prescription of statin drugs and statin contraindicated CYP3A4 inhibitor drugs (SCCID), and the risk of liver injury using data from a sample of the UK adult population, adjusting for potential confounders using the Self-controlled case-series design Objectives To asses and quantify the association between co-prescription of statin drugs and SCCID and first liver injury event. To assess the confounding effect of age in the association between co-prescription of statin drugs and SCCID and the risk of liver injury. Objectives To assess the effect on the risk estimates with regard to changing the length of the carry-over risk periods. To assess the assumptions of the case-series method as a way of checking its validity for the current study. The Health Improvement Network (THIN) Database Primary care in UK has a very comprehensive coverage of the population: 98% registered with a general practitioner (GP) Patient visit results in: offer advice, prescribe drug, refer to a specialist or further tests Medical and prescription data are recorded Presc data:- dosage; prescription quantity; amount; free text Several databases: GPRD, THIN, QResearch THIN, large GP database, longitudinal patient records retrieved from practicing GPs across UK Data collection began, 2003 (1988); The Health Improvement Network (THIN) Database By August 2006, data from 326 practices, 5.5m patients, 2.5 actively registered, formed 4% of the UK population. By Jan, 2011; 503 practices, 9.15m patients, 3.54 actively registered; representing ~6% of the UK population. THIN demographically representative of the UK Pop. Patient information organised in: Demographics: gender, dob, date of registration/leaving practice Diagnosis: medical diagnosis, date of diagnosis, free text (if available) Prescribing: presc and presc dates, formulation, strength, qty and dosing instruction. AHI: Info on lifestyle and health factor e.g smoking, alcohol intake etc SES/SEP What is the case-series method? The self-controlled case series (SCCS) method is an alternative study method for investigating the association between a transient exposure and an adverse event. The method was developed to study adverse reactions to vaccines (MMR Vaccine-1992). The method uses only cases, no separate controls are required as the cases act as their own controls. Whitaker et al, 2005 Whitaker et al, 2005 What is the case-series method? Time-varying confounding factors such as age can be allowed for by dividing up the observation period further into age categories. An advantage of the method is that confounding factors that do not vary with time, such as genetics, location, socio-economic status are controlled for implicitly. Each case's given observation time is divided into control and risk periods. Risk periods are defined during or after the exposure. Then the method finds a relative incidence, that is, the incidence in risk periods relative to the incidence in control periods. Whitaker et al, 2005 Whitaker et al, 2005 Fig. 1 A general illustration of a case's observation time divided into control, risk periods and age-bands Control period Case series: Summary It is a conditional cohort method: exposures are regarded as fixed, event times as random. Follow-up is not censored at event. The method can be used with independent recurrent events, or uncommon non-recurrent events. Only cases are required: estimation is within-individuals. The analysis is self-matched, thus eliminating the effect of fixed confounders. It has been programmed in standard statistics packages. Whitaker et al, 2005 Whitaker et al, Stat Methods Med Res. 2009 Feb;18(1):7-26 However… The method has three stringent assumptions: Independent but recurrent events within an individual The occurrence of an event must not alter the probability of subsequent exposure. The occurrence of the event of interest must not censor or affect the observation period. If recurrent events are not independent yet the occurrence of a first event is rare, then the method can be applied using just the first event. More details on the Website (created by Heather Whitaker)http://statistics.open.ac.uk/sccs/papers.htm Tutorial paper: Whitaker et al., Statist. Med. 2006, 25: 1768 – 1797 Other papers: semi-parametric model: avoids mis-specification of age specific baseline incidence, (Farrington CP and Whitaker HJ, 2006) sample size estimation, (Musonda et al, 2006) small sample performance (Musonda et al, 2007) Example datasets and analysis files in Stata, SAS, GENSTAT, GLIM and R. The case series approach using THIN Dataset Examples of four possible timings of the outcome event liver injury for a patient in a follow-up period Fig. 4 SCCS Definitions Drug exposures Statin drug alone ‘may be’ statin drug alone SCCID exposure Co-prescription of statin and SCCID-main exposure of interest -repeat and multiple drug exposures Outcome Liver injury in the observation period Statin alone and ‘maybe’ statin alone exposure definition Fig. 2 Figure showing the start and stop points of statin drug; and restart of statin therapy in the observation period. After restart of statin therapy, the last prescription in this figure was within six months to the end of observation period (implying continuous therapy). Definition of repeat statin only exposure, and multiple statin drug exposure in the observation period Fig. 3 Case series design can handle both repeat and multiple exposure periods. Single variable to indicate that…..0,1,2,3,4 Participants and Data management (DM) Aged ≥18yrs at entry into the study Diagnosed with DILI ≥ 9moths after registration with practice Had ≥1 presc of statin/SCCID in the obs prd DM Statin exposure-cont. unless interval >6m SCCID-prescription duration Exposure periods-See Fig 5 An illustration of an individual case timeline with exposures to single drugs and co-prescription Event, Liver Injury Fig. 5 Data Management: Exposure periods: continuous exposure to statin alone, SCCID alone or co-prescription of statin and SCCID Overlapping risk periods: In the case of C, if an event occurs at any point within C, then that event will be classified as exposed to co-prescription of statin and SCCID. This means co-prescription takes precedence, but does not necessarily replace exposure to statin drugs alone. Case series: Results (1) Rate ratios of first liver injury event in the four possible drug exposure periods in a patient’s timeline given seven-days carry-over period Rate ratios of first liver injury event in the four possible drug exposure periods in a patient’s timeline given seven-days carry-over period Case series: Results (2) Summary of the sensitivity analyses results with the seven-day carry-over period Main findings/discussions Sig. higher rate of first liver injury event in the periods of: co-prescription of statin drugs and SCCID ‘may be’ statin drugs alone SCCID alone Compared to baseline (unexposed periods) Rates attenuated with increased carry-over intervals No evidence to support hypothesis….. Case series: No evidence to support the hypothesis of higher risk of first liver injury event being associated with co-prescription of statin drugs and SCCID compared to the risk of prescribing statin drugs alone or SCCID alone. Strengths and limitations Strengths of the study: Dealing with both unmeasured and some measured confounding effect…residual confounding minimised; good face validity; data used has been validated; e.t.c Confounding by indication (sensitivity analysis-7days pre-exposure period) Possible weaknesses: Misclassification of exposure periods, patient adherence not measured but assumed once drug was prescribed. True risk periods unknown (sensitivity analysis) Absolute risks are not estimated. Overall Summary Although the study has shown evidence of an association between periods of exposure to co-prescription of statin drugs and SCCID; statin drugs alone; or SCCID alone; compared to baseline (no drug), there is no evidence that periods of co-prescription of statin drugs and SCCID increased the risk of liver injury than when compared to periods of statin drugs alone or SCCID alone These results, were less prone to the problem of confounding bias (in cohort design), and the validity of the results have been assessed thro sensitivity analyses of the stringent assumptions. Results in context: implications Lack of increased risk of liver injury as hypothesised in the study may be due to: Induction of alternative metabolic pathways Selective medication taking by patients (may be influenced by GP advice) Clinicians to maintain close monitoring of statin drug users Prescribers may use the results to make more informed decisions in prescribing SCCID to patients already on statin drug therapy. Selected References 1. C. P. Farrington, H.J.W., Semiparametric analysis of case series data. Journal of the Royal Statistical Society: Series C (Applied Statistics), 2006. 55(5): p. 553-594. 2. Farrington, C.P., et al., Self-controlled case series analysis with event-dependent observation periods. Journal of the American Statistical Association, 2011(0): p. 1-10. 3. Farrington, C.P. and M.N. Hocine, Within-individual dependence in self-controlled case series models for recurrent events. Journal of the Royal Statistical Society: Series C (Applied Statistics), 2010. 59(3): p. 457-475. 4. Farrington, C.P., H.J. Whitaker, and M.N. Hocine, Case series analysis for censored, perturbed, or curtailed post-event exposures. Biostat, 2009. 10(1): p. 3-16. 5. Musonda, P., et al., Self-controlled case series analyses: Small-sample performance. Computational Statistics & Data Analysis, 2008. 52(4): p. 1942-1957. 6. Whitaker, H.J., et al., Tutorial in biostatistics: the self-controlled case series method. Stat Med, 2006. 25(10): p. 1768-97. 7. Whitaker, H.J., M.N. Hocine, and C.P. Farrington, The methodology of self-controlled case series studies. Stat Methods Med Res, 2009. 18(1): p. 7-26. Thanks to: Bloomsbury consortium & JKUAT(financial support) Research supervisors Dr. Mariam Molokhia Dr. Dorothea Nitsch Prof. Nick Barber General Practitioners Patients who provided data for research CEGEDIM strategic staff (THIN database)