Primary care BMJ: first published as 10.1136/bmj.323.7314.666 on 22 September 2001. Downloaded from Antidepressants as risk factor for ischaemic heart disease: case-control study in primary care Julia Hippisley-Cox, Mike Pringle, Vicky Hammersley, Nicola Crown, Alison Wynn, Andy Meal, Carol Coupland Division of General Abstract disease in men from a study conducted in a single Practice, University practice.5 This association may have been related to use of Nottingham, Objectives To determine whether antidepressants are Nottingham of antidepressant drugs, although our sample was too NG7 2RD a risk factor for ischaemic heart disease and to small to be certain. Julia Hippisley-Cox compare the risk for different subgroups of Tricyclic antidepressants are not recommended in senior lecturer in antidepressants and individual antidepressants. 6 general practice patients with known ischaemic heart disease, mainly Design Case-control study. 7 Mike Pringle because of their arrhythmogenic activity. However, professor of general Setting Nine general practices recruited from the their potential role in the aetiology of ischaemic heart practice Trent Focus Collaborative Research Network. disease is unclear.8–10 A case-control study of fatal myo- Vicky Hammersley Participants 933 men and women with ischaemic research network cardial infarction in young women found an odds ratio coordinator, Trent heart disease matched by age, sex, and practice to of 16.9 for the use of psychotropic drugs.8 Conversely, Focus 5516 controls. a cohort study found that the association between Alison Wynn Main outcome measure Adjusted odds ratio for ischaemic heart disease and tricyclic antidepressants researcher in general ischaemic heart disease calculated by logistic practice probably reflected a primary relation between depres- Carol Coupland regression. sion and ischaemic heart disease.9 Another study asso- senior lecturer in Results Odds ratios for ischaemic heart disease were statistics ciated tricyclic antidepressants with increased risk of significantly raised for patients who had ever received myocardial infarction, although it did not distinguish Collingham http://www.bmj.com/ a prescription for tricyclic antidepressants even after between drugs individually and those in combination, Medical Centre, diabetes, hypertension, smoking, body mass index, Collingham, and it focused on myocardial infarction rather than on Nottinghamshire and use of selective serotonin reuptake inhibitors had first presentation of ischaemic heart disease.11 We NG23 7LB been adjusted for (1.56; 95% confidence interval 1.18 aimed to determine whether antidepressants are a risk Nicola Crown to 2.05). Patients who had ever taken dosulepin researcher factor for ischaemic heart disease and compare the risk (dothiepin) had a significantly raised odds ratio for for different subgroups of antidepressants and School of Nursing, ischaemic heart disease after adjustment for Medical School, individual antidepressants. Queen’s Medical confounding factors and use of other antidepressants Centre, Nottingham (1.67, 1.17 to 2.36). There was no significant increase on 24 September 2021 by guest. Protected copyright. NG7 2UH in the odds ratios for amitriptyline, lofepramine, and Andy Meal Participants and methods lecturer selective serotonin reuptake inhibitors in multivariate We recruited nine general practices from the Trent Correspondence to: analysis. Increasing maximum doses of dosulepin Julia Hippisley-Cox were associated with increasing odds ratios for Focus Collaborative Research Network, which has julia.hippisley-cox@ ischaemic heart disease. Similarly, there was a been shown to be representative of other practices in nottingham.ac.uk significant positive trend associated with increasing Trent (unpublished data). Practices met minimum criteria for data quality: these were minimum levels of BMJ 2001;323:666–9 numbers of prescriptions of dosulepin (adjusted odds ratio 1.52 for 1 prescription, 1.39 for 2-3, and 1.96 for recording of nine chronic diseases (for example, preva- >4, P < 0.002). lences of 4.3% for ischaemic heart disease, 2.7% for 12 Conclusion There is good evidence for an association diabetes, and 10.3% for hypertension) ; lifestyle data between dosulepin and subsequent ischaemic heart and blood pressure recorded in more than 50% of disease and for a dose-response relation. adults; and use of practice computer for prescribing. The study was approved by Trent multicentre research Introduction ethics committee and local research ethics committee. This was a matched case-control study. We Major depression is the fourth most important identified incident cases from the practice computer contributor to disability adjusted life years worldwide.1 records for 1 January 1995 to 31 December 1999. Over 45% of patients in hospital after a myocardial Cases were men and women who had a recorded diag- infarction have depression,2 and it is an independent nosis of ischaemic heart disease (including angina, risk factor for increased mortality3 and morbidity4 after myocardial infarction, and coronary artery surgery) or myocardial infarction. In 1998, we reported evidence were receiving repeat prescriptions for nitrates.13 We for depression as a risk factor for ischaemic heart included only cases who had been registered with the 666 BMJ VOLUME 323 22 SEPTEMBER 2001 bmj.com Primary care BMJ: first published as 10.1136/bmj.323.7314.666 on 22 September 2001. Downloaded from practice for more than five years before ischaemic tors; between dosulepin (dothiepin) and amitriptyline, heart disease was diagnosed and whose first recorded and between dosulepin and lofepramine. diagnosis was at least five years after the date on which We adjusted for the potential confounding effects the practice had its current computer installed. of diabetes, hypertension, body mass index, and smok- Controls were patients who had never had a ing status by multivariate analysis. We present the recorded diagnosis of ischaemic heart disease. We iden- unadjusted and adjusted odds ratios associated with tified four to six controls, matched for age and sex, for each dose and duration category. Dose-response each case. Controls were selected by finding the patients relations were tested for trend. A case-control set was closest in age (years) from an ordered list of patients cur- excluded if the information for either the case or all its rently registered with the same practice. Each control controls was not known for the variable in question. was allocated to only one case. Controls had to be alive and registered with the same practice on the date that Calculation of sample size their matched case was diagnosed with ischaemic heart Assuming 10% use of tricyclic antidepressants within disease and for the five years before this. the preceding five years, we calculated that we needed 804 case-control sets (one case to four controls) to Data collection show an odds ratio of 1.5 for the use of antidepressants We extracted computerised data for cases and controls before the onset of ischaemic heart disease with a 95% before the date of diagnosis (or diagnosis of matched 15 14 power at 5% significance. We estimated that we would case) using MIQUEST. The data comprised name, need nine general practices with a total population of dose, frequency, and dates of issue of all antidepressant 70 000 to ensure that we could identify 800 incident drugs; Read codes and dates of onset for depression, cases during the specified five years. ischaemic heart disease, diabetes mellitus, and hyper- tension; age; sex; body mass index; most recently recorded smoking status (current smoker, former Results smoker, non-smoker, or not recorded); and registration Characteristics of study population date. We coded antidepressants according to the classifi- Among the 74 948 registered patients, there were 933 cation in the British National Formulary (March 2000). incident cases of ischaemic heart disease which met We determined the time (in years) between the last pre- our inclusion criteria. We matched 516 men with scription for each antidepressant and the date of ischaemic heart disease to 3081 male controls and 417 diagnosis of the case. women to 2435 female controls. We had a mean of 7.5 Statistical methods (SD 1.5) years of prescription data for cases and 7.4 We calculated odds ratios with 95% confidence (SD 1.7) years for controls before the date of diagnosis. intervals using conditional multiple logistic regression In total, we had 47 551 person years of prescription analysis for individually matched case-control studies and morbidity data. Table 1 shows the numbers of (Stata, version 5). Our outcome variable was ischaemic cases and controls and their baseline characteristics. heart disease. The main variable of interest was use of Table 2 shows the odds ratios for ischaemic heart http://www.bmj.com/ any antidepressant drug before diagnosis. We com- disease associated with the use of antidepressant drugs. pared the odds ratios and 95% confidence intervals Patients with a Read code for depression but no associated with each British National Formulary recorded use of antidepressants and those who had category of antidepressants singularly and in combina- ever received monoamine oxidase inhibitors or a drug tion. We tested for an interaction between tricyclic anti- from British National Formulary section 4.3.4 (other depressants and selective serotonin reuptake inhibi- antidepressants) did not have significantly raised odds ratios for ischaemic heart