Hans Liedholm

Prescriptions with potential drug interactions dispensed at Swedish pharmacies in January 1999: cross sectional study

The growing use of pharmacological agents means that drug interactions are of increasing interest for public health.1 Monitoring of potential drug interactions may improve the quality of drug prescribing and dispensing, and it might form a basis for education focused on appropriate prescribing.

Effects of systematic education on heart failure patients' knowledge after 6 months. A randomised, controlled trial.

Many procedures for patient education are introduced in clinical practice without proper evaluation in randomised trials.

Survival after initial hospitalisation for heart failure: a multilevel analysis of patients in Swedish acute care hospitals

STUDY OBJECTIVE Although national variation in short-term prognosis (that is, 30 day mortality) after a patients first hospitalisation for heart failure may depend on individual differences between patients, dissimilarities in hospital practices may also influence prognosis. This study, therefore, sought to disentangle patient determinants from institutional factors that might explain such variation. DESIGN A multilevel logistic regression modelling was performed with patients (1st level) nested in hospitals (2nd level). Institutional effects (that is, 2nd level variance and intra-hospital correlation) were calculated unadjusted and adjusted for specific patient (that is, age and previous diseases) and institutional (that is, size of hospital) characteristics. Patients were followed up until death or 30 days from hospital admission. SETTING Hospitals in Sweden. PATIENTS The study identified all the 20 420 men and 17 923 women (ages 65 to 85) admitted to the 90 acute care hospitals in Sweden during the period 1992–1995 for their first hospitalisation attributable to heart failure. MAIN RESULTS Patient age and previous diseases (particularly senile dementia) were major determinants of impaired prognosis. Institutional factors explained only 1.6% and 2.3% of the total variation in 30 day mortality in men and women, respectively. These modest institutional effects remained after adjusting for patient age and previous diseases, but were in part explained by hospital size. CONCLUSIONS National variation in short-term prognosis after an initial hospitalisation for heart failure was mainly explained by differences between patients, with hospital factors playing a minor part. Of the latter, hospital size seemed to emerge as one determinant (that is, the greater the number of patients, the better the individual prognosis).

Incidence of myocardial infarction in elderly men being treated with antihypertensive drugs: population based cohort study.

Abstract Objective: To analyse the association between use of antihypertensive treatment, diastolic blood pressure, and long term incidence of ischaemic cardiac events in elderly men. Design: Population based cohort study. Baseline examination in 1982-3 and follow up for up to 10 years. Setting: Malmo, Sweden. Subjects: 484 randomly selected men born in 1914 and living in Malmo during 1982. Main outcome measures: Observational comparisons of incidence rates and rate and hazard ratios of ischaemic cardiac events (myocardial infarction or death due to chronic ischaemic cardiac disease). Results: The crude incidence rate of ischaemic cardiac events was higher in those subjects who were taking antihypertensive drugs than in those who were not (rate ratio 2.6 (95% confidence interval 1.7 to 3.9)). After adjustment for potential confounders (differences in baseline smoking habits, blood pressure, time since diagnosis of hypertension, ischaemic or other cardiovascular disease, hypercholesterolaemia, hypertriglyceridaemia, diabetes mellitus, obesity, and raised serum creatinine concentration) this rate was reduced but still raised (hazard ratio 1.9 (1.0 to 3.7)). In men with diastolic blood pressure >90 mm Hg, antihypertensive treatment was associated with a twofold increase in the incidence of ischaemic cardiac events (rate ratio 2.0 (1.1 to 3.6)), which vanished after adjustment for potential confounders (hazard ratio 1.1 (0.5 to 2.6)). In those subjects with diastolic blood pressure </=90 mm Hg, antihypertensive treatment was associated with fourfold increase in incidence (rate ratio 3.9 (2.1 to 7.1)), which remained after adjustment for potential confounders (hazard ratio 3.8 (1.3 to 11.0)). Conclusion: Antihypertensive treatment may increase the risk of myocardial infarction in elderly men with treated diastolic blood pressures </=90 mm Hg.

Association of outpatient utilisation of non-steroidal anti-inflammatory drugs and hospitalised heart failure in the entire Swedish population

Abstract. Objective: Individual-based studies on restricted geographical settings have suggested that non-steroidal anti-inflammatory drugs (NSAIDs) may precipitate congestive heart failure. As NSAID use is very extensive, it might increase the occurrence of symptomatic heart failure in the general population. Therefore, in order to study the impact of NSAID utilisation (prescribed and over the counter) on hospitalised heart failure in an entire country (Sweden), we performed an ecological analysis, a design appropriate for studying large geographical areas. Methods: We employed weighted (population size) ecological linear regression to study the association between outpatient utilisation of NSAIDs during 1989–1993 and hospitalised heart failure in 1993 in 283 of Swedens 288 municipalities. Data were adjusted for age and gender proportions, socio-economic factors, latitude and utilisation of cardiovascular drugs, aspirin, low-dose aspirin and paracetamol. Results: The unadjusted relative risk of hospitalised heart failure for each increase of one standard deviation of NSAID utilisation (5.8 defined daily doses/1000 inhabitants/day) was 1.23 [95% confidence interval (CI) 1.18, 1.27]. After adjustments, the relative risk was 1.08 (95% CI 1.04, 1.12); the corresponding values if aspirin (non-low-dose) was included as an NSAID were 1.26 (95% CI 1.23, 1.28) and 1.07 (95% CI 1.04, 1.10). There was no such adjusted association with the utilisation of paracetamol – 0.95 (95% CI 0.92, 0.98). Conclusion: The NSAID–heart failure association already established by individual-based studies on restricted geographical settings was corroborated in the present ecological study based on the whole population of an entire country (Sweden). Efforts should be made to promote a rational use of NSAIDs in the general population.

Increased risk of ischaemic heart disease mortality in elderly men using anxiolytics-hypnotics and analgesics

AbstractObjectives: An increased risk of all-cause and cardiovascular mortality in users of anxiolytic-hypnotic drugs (AHD) has been reported, and use of analgesics may be an additional factor. Therefore, we examined the association of AHD and analgesic use, alone and in combination, with all-cause and ischaemic heart disease (IHD) mortality. Methods: Multivariate 10-year survival analysis in a population based cohort of 500 men born in 1914. Relative risks (RR) were adjusted by relevant confounders (blood pressure, serum cholesterol, diabetes mellitus, smoking habit, high alcohol consumption, history of previous IHD, cancer, and other diseases). Results: The RR of both all-cause and IHD mortality were significantly increased among those using both AHD and analgesics compared to those who took neither of these drugs: RR=1.8 for all-cause mortality, and RR=2.7 for IHD mortality. Conclusion: Although the number of cases was small, warranting interpretative caution, the current study suggests that the combined use of AHD (mainly benzodiazepines) and analgesics seems to be associated with an increase in all-cause and IHD mortality in elderly men.

Low-dose aspirin to pregnant women: Single dose pharmacokinetics and influence of short term treatment on bleeding time

Single dose pharmacokinetics of 75 mg aspirin was investigated in two groups of ten women with clinically normal pregnancies. Eleven non-pregnant subjects in the same age were controls. In group A, gestational age was 27-30 completed weeks, and in group B, 36-39 weeks. Venous blood samples were taken before and up to 240 minutes after the intake of the aspirin. Liquid chromatographic assays for acetylsalicylic acid (ASA) and its metabolite, salicylic acid (SA), was performed. The pharmacokinetics of ASA and SA were similar in group A and B but pregnant subjects had a slower uptake and a lower peak level than controls. The late elimination phase for their compound did not differ between the groups. Nine pregnant women with normal pregnancies had their bleeding time measured by a modified Ivy technique using a Simplate II device before, at the end of, and two weeks after daily administration of 75 mg ASA for two weeks. All had a normal bleeding time before and two weeks after the end of the medication. Eight of the nine subjects had an increased bleeding time by Ivy tests, (p < 0.01) whereas the bleeding time assessed by Dukes method was within normal limits. These studies suggest that during pregnancy changes of the uptake rate and distribution volume modulate the pharmacokinetics of ASA and that this drug given in low dosage to gravidae marginally alters their platelet function.

A placebo-controlled dose-response study of felodipine extended release in hypertensive patients.

This placebo-controlled study assessed antihypertensive effect and tolerability of two dose levels of an extended release (ER) formulation of felodipine (Plendil), given once daily to patients in primary health care. The patients had mild to moderate hypertension and were randomized to receive felodipine ER (FER) 20 mg (n = 50), FER 10 mg (n = 50), or placebo (n = 51) in a 4-week, double-blind, parallel-group multicenter study. After 4 weeks, the 24-h reduction in supine diastolic BP (DBP) was greater (p < 0.01) in both FER groups (7 ± 6 and 8 ± 5 mm Hg) than in the placebo group (4 ± 6 mm Hg). The 24-h reduction in supine systolic BP (SBP) was greater (p < 0.01) in the FER 20-mg group (14 ± 11 mm Hg), but not in the FER 10-mg group, than in the placebo group (8 ± 11 mm Hg). No significant difference in blood pressure (BP) was found between FER 10 and 20 mg. Heart rate (HR) did not differ between any of the groups, nor did body weight or routine laboratory parameters. During felodipine treatment, 17 patients (12 receiving FER 20 mg) were withdrawn mostly because of vasodilatory side effects such as headache and ankle edema. We conclude that FER 10 mg and 20 mg once daily had an antihypertensive 24-h effect and that FER 10 mg may be more suitable as initial dose.

Pharmacological treatment of systolic heart failure

Sir—The results of the MERIT-HF study (June 12, p 2001) add to knowledge on the pharmacological treatment of systolic heart failure. A similar trial of another selective -blocker, bisoprolol, was published earlier this year. The CIBIS-II study has received very little criticism. Now, with the publication of the MERIT-HF trial, we want to question the external validity of the two trials and discuss aspects of the MERIT-HF study. According to CONSORT guidelines for reports of randomised controlled trials, emphasis is put on the situation before randomisation—ie, number of eligible patients, the number of patients not randomised, and the reasons for non-randomisation. In both these heart failure trials no data are given about number of eligible patients. This point may seem trivial, but because the treatment of heart failure with -blockers has side-effects, especially in patients with advanced disease, many patients are probably never regarded as eligible, and therefore not included. How many patients were initially involved and where did they come from? The omission of information on eligible patients is hard to understand, because the external validity depends on the representativeness of those patients included. Some limitations of the two studies were outlined by Norman Sharpe in his commentary, but he did not discuss the presentation of the trials. Furthermore. the investigators of the MERIT-HF study (a third representing the sponsor) emphasise that metoprolol is a “lipid soluble -blocker”, probably inferring that positive data on -blockers in treatment of heart failure are collected from trials on lipidsoluble -blockers only. T h e octanol/buffer partition coefficient of the free form of the drug, which is usually taken as an indication of the lipid solubility of the compound, has not yet proved to have real meaning in this context. If we take data from studies on the effects of -blockers after myocardial infarction, recently extensively reviewed, and plot octanol/buffer coefficients against pooled odds ratios for death, the importance of lipid solubility of blockers (figure) is not supported. Sufficient data are lacking in both situations and should, until confirmed, be regarded more as a redundant message intended for the market.