Thomas M. MacDonald

Taking Glucocorticoids by Prescription Is Associated with Subsequent Cardiovascular Disease

Context Patients who take glucocorticoids appear to have an increased risk for cardiovascular disease. However, data about the magnitude of this increased risk are lacking Contribution In this large, population-based study, the use of glucocorticoids was associated with an increased risk for cardiovascular events, with a clear dose-response relationship. Patients who received high-dose glucocorticoids were more than 2.5 times as likely as patients who did not use glucocorticoids to experience a cardiovascular event. Implications These data will help clinicians estimate cardiovascular risk among patients who require glucocorticoids. The Editors Glucocorticoids are commonly used as anti-inflammatory and immunosuppressive therapy in diseases such as asthma, inflammatory bowel disease, and inflammatory arthritis. Well-known adverse effects of glucocorticoids include hypertension, diabetes mellitus, and obesity (1-3), all of which are independent risk factors for cardiovascular disease. The principal physiologic glucocorticoid is cortisol. Increased cortisol secretion and action, even within the physiologic range, is associated with several risk factors for cardiovascular disease (4, 5). Indeed, studies have proposed that subclinical Cushing syndrome may be an important cardiovascular risk factor (6, 7). However, whether, and to what extent, the adverse effects of exogenous glucocorticoids on these risk factors for cardiovascular disease cause cardiovascular morbidity and death has not been established (8, 9). This is not predictable, especially since glucocorticoids may also have cardioprotective effects mediated by their anti-inflammatory and antiproliferative actions in the vessel wall (10, 11). We tested the hypothesis that users of exogenous glucocorticoids have an increased risk for cardiovascular disease. In particular, we hypothesized that high doses will be associated with cardiovascular disease, while doses equivalent to or below the physiologic range of endogenous glucocorticoid secretion may be compensated for by decreased cortisol levels and will not incur excessive risk. We have tested this by using the MEdicines MOnitoring unit (MEMO) record linkage database to compare people who were exposed and not exposed to glucocorticoid therapy. Methods We performed this study in the Tayside region in Scotland by using the MEMO record linkage database. The MEMO database covers a geographically compact population and serves about 400000 patients in the National Health Service (NHS) in Scotland, 97% of whom are white. The NHS in Scotland is tax-funded and free at the point of consumption and covers the entire population. In Tayside, almost no health care is delivered without the NHS. The data collection methods for this database have previously been described (12). In brief, this database contains several data sets, including all dispensed community prescriptions, hospital discharge data, mortality data, biochemistry data, and other data, that are linked by a unique patient identifier, the community health index number. These data are made anonymous for the purposes of research, as approved by the Tayside Caldicott Guardians (a group appointed by the government to protect the confidentiality of medical records). The Tayside committee on research medical ethics also approved the project. We cleaned and validated all data before analysis. We included all patients who resided in Tayside and registered with a general practitioner in January 1993, who were 40 years of age or older, and who remained a resident in Tayside until December 1997 or who died during the study period. Definitions of Exposure to Glucocorticoids Exposed and Comparator Cohorts All patients who received 1 or more dispensed prescriptions for glucocorticoids (including inhaled steroids, topical steroids, oral and parenteral steroids, rectal application steroids, and nasal steroids) between July 1993 and December 1996 formed the exposed cohort. They entered the study at their date of first prescription. The rest of the study sample made up the comparator cohort. We excluded patients who were hospitalized for inflammatory bowel disease and chronic obstructive airways disease during the follow-up period because they may have been given glucocorticoids as hospital inpatients without the prescriptions being identified by MEMO. We generated a random date of entry to the study for each member of the comparator cohort by using a frequency-matched calendar year generated from the dates of entry to the study in the exposed cohort. We excluded patients from both cohorts if they were hospitalized for cardiovascular disease before study entry. Dose of Glucocorticoids For about two thirds of dispensed oral or systemic glucocorticoid prescriptions, we recorded the date of prescription, dose of tablets, amount dispensed, and instructions on how medication should be taken. For these prescriptions, we could determine daily exposure during prescribed courses. For the remainder, we knew the total dose dispensed but, because prescriptions were marked take as directed, could not accurately determine the daily dose and duration. We therefore calculated the average daily dose by dividing the total amount of glucocorticoid dispensed by the total number of days of observation. For multiple simultaneous formulations (oral and inhaled) of glucocorticoids, we used only the oral glucocorticoids to calculate the daily dose. We categorized glucocorticoid exposure according to average daily doses throughout the follow-up period for each patient as high (oral, parenteral, and rectal steroids with daily dosage 7.5 mg [that is, supraphysiologic doses]); medium (oral, parenteral, and rectal steroids with daily dosage <7.5 mg [that is, approximately equivalent to the physiologic range of endogenous glucocorticoid secretion]); or low (inhaled, topical, and nasal steroids with daily dosage less than the equivalent physiologic range). As a result of this calculation, we included patients who took large dosages for a short period in the medium-dose group. We calculated dose equivalents of prednisolone as follows: 1 mg of prednisolone = 5 mg of cortisone = 4 mg of hydrocortisone = 1 mg of prednisone = 0.8 mg of triamcinolone = 0.8 mg of methylprednisolone = 0.15 mg of dexamethasone = 0.15 mg of betamethasone (13). The MEMO database does not collect information for prescriptions dispensed in hospitals. We considered participants hospitalized for asthma, inflammatory bowel disease, or chronic obstructive pulmonary disease (disorders usually treated with high-dose glucocorticoids in the hospital) as being exposed to a typical dosage of glucocorticoids (30 mg/d, prednisolone) during that period. Analysis of Events during Glucocorticoid Exposure (On Treatment vs. Off Treatment) We did a subgroup analysis of those patients for whom we had data on daily dose of glucocorticoid exposure. For each patient, we divided exposure to glucocorticoid into the time that the patient was exposed (on treatment) and the time that the patient was not exposed (off treatment). We then temporally related these periods to the occurrence of cardiovascular events. Incident versus Prevalent Use For each patient in the cohort exposed to glucocorticoids, we used the 6 months before entry to the study as a screening period. We classified patients who did not receive glucocorticoids during this period as incident users of glucocorticoids and patients who received glucocorticoids during this period as prevalent users. Continuous versus Intermittent Use We did an analysis comparing cardiovascular risk in continuous use (180 days between prescriptions) versus intermittent use (>180 days between prescriptions). Exposure by Disease Indication We identified patients with chronic obstructive pulmonary disease if they were hospitalized for asthma or chronic obstructive pulmonary disease or were prescribed an inhaled steroid or bronchodilator drug before study entry. We identified patients with inflammatory bowel disease if they were hospitalized for colitis or were prescribed a rectal steroid preparation before study entry. We identified patients with inflammatory arthritis if they were hospitalized for inflammatory arthritis or were prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs before study entry. Outcome Variables We collected the outcome data on each patient until 31 December 1997. The outcome of the study was a cardiovascular event defined as the composite end point of hospitalization with a primary diagnosis of myocardial infarction, angina, angioplasty or coronary revascularization, stroke, transient ischemic attack, congestive cardiac failure, or cardiovascular death during follow-up. We censored patients at their first event if they had several events. We ascertained diagnoses of myocardial infarction, angina, angioplasty and coronary revascularization, stroke, transient ischemic attack, and congestive cardiac failure from the hospital discharge diagnosis data, which were validated (14) in the Scottish Morbidity Record 1 by primary International Classification of Diseases, Ninth or Tenth Revisions, codes. We also ascertained diagnoses of angioplasty and coronary revascularization by the code of classification of surgical operations and procedures. We also obtained the death certification data for all Tayside residents who died. Statistical Analysis We counted events that occurred during the study period and compared rates of events between cohorts. We used the Poisson regression model to investigate the association between glucocorticoid exposure and cardiovascular outcome. We included the following covariates: age at study entry; sex; social deprivation; use of angiotensin-converting enzyme inhibitors, anticoagulants, antiplatelet agents, -blockers, -blockers, calcium-channel blockers, cardiac glycosides, diuretics, nitrates, lipid-lowering drugs, hormone replacement the

Association of road-traffic accidents with benzodiazepine use

BACKGROUND Psychomotor studies suggest that commonly prescribed psychoactive drugs impair driving skills. We have examined the association between the use of psychoactive drugs and road-traffic accidents. METHODS We used dispensed prescribing as a measure of exposure in a within-person case-crossover study of drivers aged 18 years and over, resident in Tayside, UK, who experienced a first road-traffic accident between Aug 1, 1992, and June 30, 1995, and had used a psychoactive drug (tricyclic antidepressant, benzodiazepine, selective serotonin-reuptake inhibitor, or other psychoactive drug [mainly major tranquillisers]) between Aug 1, 1992, and the date of the accident. For each driver, the risks of having a road-traffic accident while exposed and not exposed to a drug were compared. FINDINGS 19386 drivers were involved in a first road-traffic accident during the study period. 1731 were users of any study drug. On the day of the accident, 189 individuals were taking tricyclic antidepressants (within-patient exposure odds ratio for an accident 0.93 [95% CI 0.72-1.21]), 84 selective serotonin-reuptake inhibitors (0.85 [0.55-1.33]), 235 benzodiazepines (1.62 [1.24-2.12]), and 47 other psychoactive drugs (0.88 [0.62-1.25]). The risk associated with benzodiazepine use decreased with increasing drivers age and was greater when the breath test for alcohol was positive. A dose-response relation was evident with benzodiazepines. The increased risk with benzodiazepines was significant for long-half-life drugs, used as anxiolytics, and for short-half-life hypnotics (all zopiclone). INTERPRETATION Users of anxiolytic benzodiazepines and zopiclone were at increased risk of experiencing a road-traffic accident. Users of anxiolytic benzodiazepines and zopiclone should be advised not to drive.

Adherence to insulin treatment, glycaemic control, and ketoacidosis in insulin-dependent diabetes mellitus

BACKGROUND Intensive insulin treatment effectively delays the onset and slows the progression of microvascular complications in insulin-dependent diabetes mellitus (IDDM). Variable adherence to insulin treatment is thought to contribute to poor glycaemic control, diabetic ketoacidosis, and brittle diabetes in adolescents and young adults with IDDM. We assessed the association between the prescribed insulin dose and the amount dispensed from all community pharmacies with the Diabetes Audit and Research in Tayside Scotland (DARTS) database. METHODS We studied 89 patients, mean age 16 (SD 7) years, diabetes duration 8 (4) years, and glycosylated haemoglobin (HbA1c) 8.4 (1.9)%, who attended a teaching hospital paediatric or young-adult diabetes clinic in 1993 and 1994. The medically recommended insulin dose and cumulative volume of insulin prescriptions supplied were used to calculate the days of maximum possible insulin coverage per annum, expressed as the adherence index. Associations between glycaemic control (HbA1c), episodes of diabetic ketoacidosis, and all hospital admissions for acute complications and the adherence index were modelled. FINDINGS Insulin was prescribed at 48 (19) IU/day and mean insulin collected from pharmacies was 58 (25) IU/day, 25 (28%) of the 89 patients obtained less insulin than their prescribed dose (mean deficit 115 (68; range 9-246] insulin days/annum). There was a significant inverse association between HbA1c and the adherence index (R2 = 0.39; p < 0.001). In the top quartile (HbA1c > 10%), 14 (64%) of individuals had an adherence index suggestive of a missed dose of insulin (mean deficit 55 insulin days/annum). There were 36 admissions for complications related to diabetes. The adherence index was inversely related to hospital admissions for diabetic ketoacidosis (p < 0.001) and all hospital admissions related to acute diabetes complications (p = 0.008). The deterioration in glycaemic control observed in patients aged 10-20 years was associated with a significant reduction (p = 0.01) in the adherence index. INTERPRETATION We found direct evidence of poor compliance with insulin therapy in young patients with IDDM. We suggest that poor adherence to insulin treatment is the major factor that contributes to long-term poor glycaemic control and diabetic ketoacidosis in this age group.

Effect of ibuprofen on cardioprotective effect of aspirin

Summary Treatment with ibuprofen might limit the cardioprotective effects of aspirin. We aimed to assess whether patients with known cardiovascular disease who take low-dose aspirin and ibuprofen have increased risk of cardiovascular mortality. We studied 7107 patients who were discharged after first admission for cardiovascular disease between April, 1989, and April, 1997, and who were prescribed low-dose aspirin (

Adherence to prescribed oral hypoglycaemic medication in a population of patients with Type 2 diabetes: a retrospective cohort study

Aims To evaluate the patterns and predictors of adherence in all patients with Type 2 diabetes in the community receiving treatment with a single oral hypoglycaemic drug. In particular, to test the hypothesis that one tablet per day is associated with better adherence than more than one.

Primary non-compliance with prescribed medication in primary care.

OBJECTIVE--To determine the rate of patients not redeeming their prescriptions (primary noncompliance) and assess the factors influencing this. DESIGN--Observational study comparing copies of prescriptions written by general practitioners with those dispensed by pharmacists and subsequent case record review. SETTING--A large rural general practice in Tayside. SUBJECTS--All 4854 patients who received prescriptions (20,921) written between January 1989 and March 1989. MAIN OUTCOME MEASURES--The rate of non-redemption of prescriptions. RESULTS--Seven hundred and two patients (14.5%) did not redeem 1072 (5.2%) prescriptions during the study period, amounting to 11.5% of men and 16.3% of women. Non-redemption was highest in women aged 16-29 (27.6% of women) and men aged 40-49 (18.3% of men). Of prescriptions issued to women for oral contraceptives 24.8% were not redeemed during the study period. In those who redeemed prescriptions 17% were not exempt from prescription charges compared with 33% of patients who failed to redeem them. The non-redemption rate was highest for prescriptions issued at the weekends, although this was a small proportion of all prescribing. Prescriptions issued by trainee general practitioners were also less likely to be redeemed. CONCLUSIONS--Non-redemption varies with age, sex, general practitioner, exemption status, and with day of the week the prescription was written. Observational studies of drug exposure can be more accurately estimated from dispensing rather than prescribing data.

Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial

Summary Background Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure. Methods In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18–79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25–50 mg), bisoprolol (5–10 mg), doxazosin modified release (4–8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and ClinicalTrials.gov number, NCT02369081. Findings Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (–8·70 mm Hg [95% CI −9·72 to −7·69]; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; −4·26 [–5·13 to −3·38]; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (–4·03 [–5·04 to −3·02]; p<0·0001) and versus bisoprolol (–4·48 [–5·50 to −3·46]; p<0·0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion. Interpretation Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition. Funding The British Heart Foundation and National Institute for Health Research.

The diabetes audit and research in Tayside Scotland (darts) study: electronic record linkage to create a diabetes register

Abstract Objectives: To identify all patients with diabetes in a community using electronic record linkage of multiple data sources and to compare this method of case ascertainment with registers of diabetic patients derived from primary care. Design: Electronic capture-recapture linkage of records included data on all patients attending hospital diabetes clinics, all encashed prescriptions for diabetes related drugs and monitoring equipment, all patients discharged from hospital, patients attending a mobile unit for eye screening, and results for glycated haemoglobin and plasma glucose concentrations from the regional biochemistry database. Diabetes registers from primary care were from a random sample of eight Tayside general practices. A detailed manual study of relevant records for the 35 144 patients registered with these eight general practices allowed for validation of the case ascertainment. Setting: Tayside region of Scotland, population 391 274 on 1 January 1996. Main outcome measures: Prevalence of diabetes; population of patients identified by different data sources; sensitivity and positive predictive value of ascertainment methods. Results: Electronic record linkage identified 7596 diabetic patients, giving a prevalence of known diabetes of 1.94% (0.21% insulin dependent diabetes, 1.73% non-insulin dependent): 63% of patients had attended hospital diabetes clinics, 68% had encashed diabetes related prescriptions, 72% had attended the mobile eye screening unit, and 48% had biochemical results diagnostic of diabetes. A further 701 patients had isolated hyperglycaemia (plasma glucose >11.1 mmol/l) but were not considered diabetic by general practitioners. Validation against the eight general practices (636 diabetic patients) showed electronic linkage to have a sensitivity of 0.96 and a positive predictive value of 0.95 for ascertainment of known diabetes. General practice lists had a sensitivity of 0.91 and a positive predictive value of 0.98. Conclusions: Electronic record linkage was more sensitive than general practice registers in identifying diabetic subjects and identified an additional 0.18% of the population with a history of hyperglycaemia who might warrant screening for undiagnosed diabetes. Key messages It has been recommended that regional registers of patients with diabetes are established in order to facilitate effective monitoring and treatment of diabetes In Tayside we created a diabetes register by record linkage of multiple data sources: all patients attending hospital diabetes clinics, all encashed prescriptions for diabetes related drugs and monitoring equipment, all patients discharged from hospital, patients attending a mobile unit for eye screening, and results for glycated haemoglobin and plasma glucose concentrations from the regional biochemistry database This register identified 7596 patients with diabetes in Tayside, giving a prevalence of diabetes of 1.94% Record linkage was more sensitive than general practice registers in ascertaining cases of known diabetes A unique patient identifier, the community health number, was fundamental for successful record linkage

Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study.

Abstract Objectives: To determine the profile of risk of upper gastrointestinal toxicity during continuous treatment with, and after cessation of, non-steroidal anti-inflammatory drugs. Design: Cohort study with a prospectively constructed, population based, record linkage database containing details of exposure to all community dispensed non-steroidal anti-inflammatory drugs and also all admissions to hospital for upper gastrointestinal diagnoses. Setting: The population of Tayside, Scotland. Subjects: 52 293 subjects aged 50 and over who received one or more non-steroidal anti-inflammatory between 1 January 1989 and 31 December 1991 and 73 792 subjects who did not receive one during the same period (controls). Main outcome measures: Admission to hospital for upper gastrointestinal bleeding and perforation, and admission for other upper gastrointestinal diagnoses. Results: About 2% of the non-steroidal anti-inflammatory cohort were admitted with an upper gastrointestinal event during the study period compared with 1.4% of controls. The risk of admission for upper gastrointestinal haemorrhage and perforation was constant during continuous non-steroidal anti-inflammatory exposure and carried over after the end of exposure. The results were similar for admissions for all upper gastrointestinal events. Conclusion: This study provides evidence that non-steroidal anti-inflammatory toxicity persists with continuous exposure. There seems to be carryover toxicity after the end of prescribing. These findings have implications for the management of patients requiring non-steroidal anti-inflammatory drugs. Key messages The risk of upper gastrointestinal toxicity associated with non-steroidal anti-inflammatory drugs is constant with continuous exposure Gastrointestinal toxicity continues for some time after treatment stops Such toxicity is common in older patients and patients with a history of upper gastrointestinal disease Non-steroidal anti-inflammatory drugs should be avoided when possible; when they are used the lowest effective dose of the least toxic drug should be used for the shortest period possible

Frequency of blood glucose monitoring in relation to glycaemic control: observational study with diabetes database.

Abstract Objectives: To investigate patterns of self monitoring of blood glucose concentration in diabetic patients who use insulin and to determine whether frequency of self monitoring is related to glycaemic control. Setting: Diabetes database, Tayside, Scotland. Subjects: Patients resident in Tayside in 1993-5 who were using insulin and were registered on the database and diagnosed with insulin dependent (type 1) or non-insulin dependent (type 2) diabetes before 1993. Main outcome measures: Number of glucose monitoring reagent strips dispensed (reagent strip uptake) derived from records of prescriptions. First recorded haemoglobin A1c concentration in the study period, and reagent strips dispensed in the previous 6 months. Results: Among 807 patients with type 1 diabetes, 128 (16%) did not redeem any prescriptions for glucose monitoring reagent strips in the 3 year study period. Only 161 (20%) redeemed prescriptions for enough reagent strips to test glucose daily. The corresponding figures for the 790 patients with type 2 diabetes who used insulin were 162 (21%; no strips) and 131 (17%; daily tests). Reagent strip uptake was influenced both by age and by deprivation category. There was a direct relation between uptake and glycaemic control for 258 patients (with recorded haemoglobin A1c concentrations) with type 1 diabetes. In a linear regression model the decrease in haemoglobin A1c concentration for every extra 180 reagent strips dispensed was 0.7%. For the 290 patients with type 2 diabetes who used insulin there was no such relation. Conclusions: Self monitoring of blood glucose concentration is associated with improved glycaemic control in patients with type 1 diabetes. Regular self monitoring in patients with type 1 and type 2 diabetes is uncommon. Key messages Several studies have indicated the importance of self monitoring of blood glucose concentration for prevention of complications in patients with diabetes Uptake of reagent strips for self monitoring of blood glucose among diabetic patients who used insulin was low, with only 20% of patients with type 1 diabetes and 17% of those with type 2 diabetes obtaining enough strips to test blood glucose concentration once daily Reagent strip uptake depends on characteristics such as age and social deprivation category, and patient groups with low uptake should be identified and targeted There was a direct association between strip uptake in the previous 6 months and glycaemic control in patients with type 1 diabetes but not in those with type 2 diabetes