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Prescribing of antidepressants in cardiovascular disease: a study using a computerised general practice data base
F Tyrer BSc. MSc. Data manager, Department of Public Health, Imperial College School of Medicine
Dept. of Public Health, Chelsea and Westminster Hospital, 4th Floor, 369 Fulham Road, London SW10 9NH, UK.
Tel 0181 746 8160 Fax 0181 746 8151 Correspondence to F Tyrer please
e-mail: f.tyrer@cxwms.ac.uk
RA Lawrenson MB.BS. MD. FAFPHM. MRCGP. Senior Lecturer in Public Health, Department of Public Health, Imperial College School of Medicine
K MacRae Ph.D. Reader in Medical Statistics, Department of Public Health, Imperial College School of Medicine
RDT Farmer MB.BS. PhD. FFPHM. MRCGP. Professor and Head of Department, Department of Public Health, Imperial College School of Medicine
SUMMARY
Background
Previous studies have found a relationship between cardiovascular disease and depression. Other studies have emphasised the potential dangers of prescribing tricyclic antidepressants to patients who have had a recent history of heart disease and recommended alternatives, mainly selective serotonin re-uptake inhibitors (SSRIs).
Method
General practice patients from throughout the UK whose records were held on a computerised data base were studied. 6,151 patients with a new 'cardiovascular event' were followed up for one year to investigate new episodes of diagnosed depression and treatment with antidepressants. 625,689 patients without cardiovascular disease were used for comparison.
Results
The risk of depression in patients with cardiovascular disease was double that found in patients without (adjusted OR=2.16, 95% CI 1.85 to 2.51). Patients with heart disease were more likely to be prescribed an SSRI than a tricyclic antidepressant (adjusted OR=1.51, 95% CI 1.08 to 2.10). However 35% of patients with a recent cardiovascular event were still prescribed a tricyclic antidepressant initially.
Conclusion
Although general practitioners preferentially prescribed SSRIs to patients with cardiovascular disease, a worrying and large minority were prescribed tricyclic antidepressants. There is a need for greater education of general practitioners to improve rational prescribing.
A number of studies have reported an association between cardiovascular disease and depression (Schleifer et al, 1989; Cassem and Hackett, 1977; Bianchi et al, 1978). Depression may be associated with non-compliance of treatment for cardiovascular disease and refusal of re-habilitation programs (Carney et al, 1995). The recognition and appropriate treatment of people with depression following heart disease may therefore be an important health intervention.
Tricyclic antidepressant drugs have been in clinical use for 40 years. They are contra-indicated in patients with pre-existing heart disease (BMA and RPSGB, 1996) mainly owing to their adverse side-effects in overdose. The potential risks of prescribing tricyclic antidepressants in therapeutic doses to patients with pre-existing cardiovascular disease include orthostatic hypotension (Freyschuss et al, 1970; Glassman et al, 1979; Kopera, 1978), proarrhythmias, predominantly as type 1A antiarrhythmic agents (Chutka, 1990), but with some risk of new arrhythmias (Bigger and Sahar, 1987) and conduction disease, with slowing of cardiac conduction and ECG changes include a prolonged PR interval (Burkhardt et al, 1978). Some patients with pre-existing first-degree block develop second-degree atrioventricular block or widening of the QRS complex on beginning a course of tricyclic antidepressants (Kantor et al, 1975).
Selective serotonin re-uptake inhibitors are similar in efficacy to tricyclic antidepressants, but have different adverse effects. Randomised controlled trials exploring the risks of SSRIs often use tricyclic antidepressants as their reference product and exclude people with pre-existing heart disease (Le Pen et al, 1994; Montgomery and Kasper, 1995). Because of this, there are few studies examining cardiovascular side-effects of SSRIs in patients with pre-existing cardiovascular disease. Those which have been done however show a favourable cardiovascular profile (Fisch 1985; Warrington and Lewis, 1992; Yokota et al, 1987; Koe et al, 1983). In the current primary care setting, SSRIs are considered to be more suitable for depressed patients with a recent history of heart disease.
Methods and Aims
The two main objectives of this study were to:
- investigate the incidence of diagnosed depression following a cardiovascular event.
- compare the prescribing of antidepressants for depression to patients with and without cardiovascular disease.
Two observational studies were carried out using the MediPlus data base. This data base holds information on almost 1.8 million patients from 151 UK practices using the Meditel system to record their clinical data up to April 1997. Records are available from 1991 to April 1997. Patient prescriptions and diagnoses are all coded as Read codes (Read and Benson, 1986) and almost all prescriptions are linked to a diagnosis. Because of the size of the data base, a Sun sparcstation 20 was required to analyse the data. An Oracle data base was used and all statistical analysis was carried out using Stata (Statacorp, 1997).
Initially, patients between the ages of 14 and 79, with a new cardiovascular event between 1st April 1995 and 31st March 1996 were identified. A cardiovascular event was defined as a diagnosis of ischaemic heart disease (including myocardial infarction and angina), conduction disorder (including atrioventricular and bundle-branch block), tachycardia, atrial fibrillation, ectopic beats or cardiac arrhythmia (including cardiac arrest and heart failure). An event was said to be new if there was no record of a cardiovascular event in the one year prior to this diagnosis. To investigate the incidence of depression following this event, patients were only included if there was also no diagnosis of depression in the one year prior to their cardiovascular event diagnosis. The records of patients meeting these inclusion criteria were followed up for one year following their event. For the comparison group, the mid-point of the study window (i.e. 1st October 1995) was used to represent the date of cardiovascular diagnosis. Thus patients in the comparison group were followed up for one year between 1st October 1995 and 31st September 1996.
The age and gender distribution of the cardiovascular event group was compared to that of the comparison group. For both groups, new cases of diagnosed depression were investigated. An unconditional logistic regression model was fitted to the data. Potential confounding variables were age and gender.
Only depressed patients who were prescribed a tricyclic antidepressant or SSRI were then investigated to determine whether there was a difference between patients with cardiovascular disease and those without in the proportion of SSRIs prescribed. An unconditional logistic analysis was again carried out to adjust for the potential confounding variables age and gender.
Results
Diagnosed depression following a cardiovascular event
6,151 patients aged between 15 and 79 had a new cardiovascular event between 1st April 1995 and 31st March 1996 and no record of depression in the previous year. 181(2.9%) of these patients were diagnosed as depressed in the year following their event. Of these, 116(64%) patients had a diagnosis of ischaemic heart disease, 35(19%) had a diagnosis of heart failure and 30(17%) had a diagnosis of cardiac arrhythmia. There were 2 patients under the age of 25 who had a cardiovascular event followed by a depression diagnosis. Both these patients had a diagnosis of supraventricular tachycardia. None of the patients had a diagnosis of heart block. Of the comparison group, 625,689 patients had no prior cardiovascular event or depression in the one year prior to 1st October 1995. 11,703(1.9%) patients had a diagnosis of depression in the following year.
The cardiovascular event and comparison groups were very different in age and gender distributions. There were a higher proportion of older patients, particularly males in the cardiovascular event group, reflecting the nature of cardiovascular disease. After analysis, a two-fold increased risk (OR=2.16, 95% CI 1.85 to 2.51) of developing diagnosed depression was found in patients who had suffered a recent cardiovascular event (Table 1) after adjustment for patient age group and gender. Gender was also significant. Women were over twice as likely (OR=2.08) to be diagnosed with depression as men.
Antidepressant prescribing among patients with and without cardiovascular disease
Of the cardiovascular patients who were diagnosed with depression, 64(35%) were prescribed tricyclic antidepressants, 85(47%) patients were prescribed SSRIs and 9(5%) patients were prescribed other antidepressants. Other prescriptions ranged from anxiolytics to vitamin supplements. All patients were prescribed medication with their diagnosis. 45(70%) of patients prescribed tricyclic antidepressants had a diagnosis of ischaemic heart disease, 11(17%) patients had a diagnosis of arrhythmia and 8(13%) had a diagnosis of heart failure. Of the comparison group, 4,257(36%) patients were prescribed tricyclic antidepressants and 5,296(45%) were prescribed SSRIs to treat their depression. 592(5%) were prescribed other antidepressants. Other prescriptions varied and not all patients were prescribed medication with their diagnosis.
Only patients who were prescribed a tricyclic antidepressant or SSRI to treat their depression were then investigated. A two sample t-test was carried out to compare the mean age of patients initially prescribed a tricyclic antidepressant with those prescribed an SSRI. Patients prescribed a tricyclic antidepressant were on average 3.56 years older (Table 2). Similarly patients who had suffered a recent cardiovascular event were more likely (OR=1.51, 95% CI 1.08 to 2.10) to be prescribed an SSRI (than a tricyclic antidepressant) after adjustment for patient age group and gender (Table Three). Age group was also significant with the older age groups less likely to be prescribed an SSRI (odds ratios 0.89, 0.77 and 0.53)
Discussion
Depression and Cardiovascular disease
Schleifer et al (1989) reported that the prevalence of depression during hospitalisation for myocardial infarction (MI) was about 45%. In our study, 2.9% of patients with recent cardiovascular disease were diagnosed with depression. This difference may be explained by the fact that patients with MI were interviewed in Schleifer's study, thus depression was more likely to be diagnosed. Our study also looked only at new episodes of depression, excluding those who had been depressed before their cardiovascular event. We found that patients were more likely to develop diagnosed depression when they had suffered a recent cardiovascular event (OR=2.16). There are two possible explanations for this:
- A cardiovascular event is associated with an increased risk of developing depression.
- A recent cardiovascular event leads to more intensive follow up by general practitioners and therefore depression is more likely to be diagnosed.
The limitations of analysing general practice data mean that there is no way of knowing which of the above applies. However previous studies such as that of Schleifer et al (1989) support the hypothesis that depression is higher in people with cardiovascular disease.
Antidepressant Prescribing
In our study, nearly 90% of patients with a diagnosis of depression were treated with an antidepressant. This suggests that some depression goes unnoticed or that general practitioners do not enter a depression diagnosis unless prescribing corresponding medication. Boydell et al (1995) commented that much of the variation in diagnosis of depression in general practice could be explained by differences in detection rates and clearly these and the degree of adherence to treatment cannot be determined in a study of this nature. A large minority (35%) of patients with a recent cardiovascular event were prescribed tricyclic antidepressants initially. Most (70%) had suffered ischaemic heart disease. This suggests that some general practitioners were not aware of or ignored the potential dangers of prescribing tricyclics to such patients. One reason that they may prescribe tricyclic antidepressants to patients with pre-existing cardiovascular disease is that the risks of further problems are minimal and the costs of SSRIs are high. However the overall prescribing costs to patients with cardiovascular disease are small, whereas one would expect the costs of hospitalisation to be higher. A trial comparing the side-effects of tricyclic antidepressants with SSRIs in a group of patients who had suffered a recent cardiovascular event would not be ethical because of the known cardiotoxicity of tricyclic products.
Sources of Bias
The difference in age and gender distribution between cardiovascular and comparison groups means that the patients with cardiovascular disease were generally older and presumably less mobile than the comparison group. Previous depression may therefore have been more likely to be detected in these patients.
The cardiovascular group were followed up for one year following their cardiovascular event. Because the comparison group had not had such an event, the mid-point of the study window was taken as an approximation of this. Patients in the cardiovascular group could therefore have been followed up to the end of March 1997, whereas all patients in the comparison group were followed up to the end of September 1996. General practitioners' diagnostic and prescribing patterns could have changed in the first or second half of the study window affecting the comparability of the groups. It seems unlikely however that diagnostic and prescribing behaviour would vary substantially over such a short period of time.
Conclusions
There are three main findings from this study.
- Patients with no recent history of depression suffering a cardiovascular event were more likely to be diagnosed with depression.
- General practitioners were more likely to prescribe selective serotonin re-uptake inhibitors to patients with cardiovascular disease than to those without.
- 35% of people with a recent cardiovascular event were still prescribed a tricyclic antidepressant initially rather than an SSRI.
The findings are consistent with the theory that general practitioners recognise the dangers of prescribing tricyclic antidepressants to patients with cardiovascular disease. However a substantial proportion of these patients were still prescribed tricyclic antidepressants. Future studies should be carried out to investigate morbidity and mortality in patients with pre-existing cardiovascular disease who were prescribed tricyclic antidepressants.
Table One
Logistic Regression of depression on a cardiovascular event, age and sex |
||
| Risk Factor | Odds Ratio (OR) | 95% Confidence Limits |
| Cardiovascular Dis. | 2.16* | 1.85, 2.51 |
| Sex=Female | 2.08* | 2.00, 2.17 |
| Age 14-27 | 1 (Reference Category) | |
| Age 28-38 | 1.42* | 1.35, 1.49 |
| Age 39-53 | 1.31* | 1.24, 1.37 |
| Age 54-74 | 0.89* | 0.84, 0.94 |
| * significant at the 5% level | Note: Age Groups based on the 25th, 50th and 75th percentiles of both groups | |
Table Two
Two sample t test on agePatients prescribed tricyclic antidepressants or SSRIs for depression |
|||||
| Variable | Mean | Std Err | t | P>{t} | 95% Confidence Interval |
| Tricyclic | 42.30 | 0.24 | 178.64 | 0.0000 | 41.84, 42.76 |
| SSRI | 38.74 | 0.20 | 196.79 | 0.0000 | 38.35, 39.12 |
| Difference | 3.56 | 0.31 | 11.67 | 0.0000 | 2.96, 4.16 |
| H0: Mean(Male) - Mean(Female) = diff = 0 | |||||
| H1: | diff < 0 | diff ~=1 | diff > 0 | ||
| t=11.668 | t=11.668 | t=11.668 | |||
| P<t=1.0000 | P>|t|=0.000 | P>t=0.0000 | |||
Table Three
Logistic Regression of SSRIs prescribed by cardiovascular disease, age and gender |
|||||
| Risk Factor | Odds Ratio (OR) | Std Err | z | P<[z] | 95% Confidence Limits |
| Sex=Female | 0.99* | 0.05 | -0.20 | 0.84 | 0.91, 1.09 |
| Cardiovascular Dis. | 1.51* | 0.26 | 2.40 | 0.02 | 1.08, 2.10 |
| Age 15-29 | 1 (Reference Category) | ||||
| Age 30-37 | 0.89* | 0.52 | -2.03 | 0.04 | 0.79, 0.9 |
| Age 38-50 | 0.77* | 0.04 | -4.64 | 0.00 | 0.69, 0.86 |
| Age 51-80 | 0.53* | 0.03 | -10.77 | 0.00 | 0.48, 0.99 |
| * significant at the 5% level | Note: Age Groups based on the 25th, 50th and 75th percentiles of both groups | ||||
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First Published 10.6.98
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Last Amended: 03/23/99
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