Ivar Aursnes

Interaction between enalapril and aspirin on mortality after acute myocardial infarction : Subgroup analysis of the cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II)

The use of angiotensin-converting enzyme (ACE) inhibitors early after an acute myocardial infarction to reduce mortality has been studied in several trials with inconsistent results. Aspirin (ASA) has become a well-documented therapeutic adjunct in patients with coronary heart disease. Attention has recently been focused on a possible interaction between ASA and ACE inhibitors. We therefore reanalyzed data from the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) to find any evidence of differential effects of the ACE inhibitor enalapril in subgroups defined by use of ASA at baseline. Logistic regression tested the multiplicative interaction. We used Rothman synergy index S, which would be equal to unity under additivity, and less than unity when suggesting antagonism, to examine the postulated interaction with departure from an additive model. Logistic regression showed that the enalapril-ASA interaction term was a significant predictor of mortality at the end of the study (p = 0.047), and was a borderline significant predictor of mortality 30 days after randomization (p = 0.085). The Rothman synergy index S was 0.66 (95% confidence interval 0.46 to 0.94) for mortality at the end of the study, and 0.68 ( 0.44 to 1.04) for 30-day mortality, indicating antagonism between enalapril and ASA with departure from an additive model. Thus, we found evidence of enalapril-ASA interaction. The effect of enalapril was less favorable among patients taking ASA than among patients not taking ASA at baseline.

Association Between Various Drugs Used for Hypertension and Risk of Acute Myocardial Infarction

We examined the relation between various drugs used for treating high blood pressure and the incidence of acute myocardial infarction with a case-control design. Four hospitals taking care of all patients in Oslo with acute myocardial infarction participated with a total of 95 hypertensive men and women under 75 years of age who had had an acute myocardial infarction. A total of 329 age and sex matched controls were hypertensive citizens in Oslo without myocardial infarction. Frequency of treatment with drugs and odds ratio of risks with these drugs were calculated. The risk (odds ratio) of myocardial infarction for drug treatment during the last five years versus non drug treatment was 0.70 (95% confidence interval 0.42-1.18). The risk for diuretics and beta-blockers tested against no treatment was 0.91 (0.52-1.61). The corresponding risk for vasodilating drugs was 0.43 (0.20-0.91). Four weeks of exposure to alpha-blockers, on the other hand, tested against other drug treatments, indicated an odds ratio of 4.62 (1.01-24.0) for individuals with a history of angina. These data confirm that treatment with diuretics and beta-blockers has only little effect on the incidence of myocardial infarction. As a whole, vasodilators are associated with a significant reduction in this incidence, but alpha-blockers enhance the risk in patients with angina.

Deficient supplies of drugs for life threatening diseases in an African community

BackgroundIn Malawi essential drugs are provided free of charge to patients at all public health facilities in order to ensure equitable access to health care. The country thereby spends about 30% of the national health budget on drugs. In order to investigate the level of drug shortages and eventually find the reasons for the drugs shortages in Malawi, we studied the management of the drug supplies for common and life threatening diseases such as pneumonia and malaria in a random selection of health centres.MethodsIn July and August 2005 we visited eight out of a total of 37 health centres chosen at random in the Lilongwe District, Malawi. We recorded the logistics of eight essential and widely used drugs which according to the treatment guidelines should be available at all health centres. Five drugs are used regularly to treat pneumonia and three others to treat acute malaria. Out-of-stock situations in the course of one year were recorded retrospectively. We compared the quantity of each drug recorded on the Stock Cards with the actual stock of the drug on the shelves at the time of audit. We reviewed 8,968 Patient Records containing information on type and amount of drugs prescribed during one month.ResultsOn average, drugs for treating pneumonia were out of stock for six months during one year of observation (median value 167 days); anti-malarial drugs were lacking for periods ranging from 42 to138 days. The cross-sectional audit was even more negative, but here too the situation was more positive for anti-malarial drugs. The main reason for the shortage of drugs was insufficient deliveries from the Regional Medical Store. Benzyl penicillin was in shortest supply (4% received). The median value for non-availability was 240 days in the course of a year. The supply was better for anti-malarial drugs, except for quinine injections (9 %). Only 66 % of Stock Card records of quantities received were reflected in Patient Records showing quantities dispensed.ConclusionWe conclude that for the eight index drugs the levels of supply are unacceptable. The main reason for the observed shortage of drugs at the health centres was insufficient deliveries from the Regional Medical Store. A difference between the information recorded on the Stock Cards at the health centres and that recorded in the Patient Records may have contributed to the overall poor drug supply situation. In order to ensure equitable access to life saving drugs, logistics in general should be put in order before specific disease management programmes are initiated.

Increased permeability of capillaries to protein during thrombocytopenia an experimental study in the rabbit

Abstract Previous investigations have shown ear lymph to increase in volume and red cell concentration in many rabbits with severe thrombocytopenia. These animals had been exposed to whole body irradiation with the ears shielded. 125 I-albumin was given intravenously on one or several occasions to 7 normal and 18 such irradiated rabbits, whereafter the rate of disappearance of the albumin from plasma during the next 1.5 hr was measured. This disappearance rate was found to be increased in those rabbits which showed thrombocytopenia and increased red cell concentration in their lymph. In seven irradiated animals, five with and two without signs of capillary leakage, an ear was cut off 3 hr after an iv injection of 125 I-albumin. The amount of labeled albumin in the extravascular space was definitely increased in all five animals with leakage but was normal in the two others. Two of the five former animals also showed a high total tissue water content. Five thrombocytopenic rabbits with capillary leakage were given a transfusion with washed platelets. This changed the albumin disappearance rate in a normal direction in all five rabbits. It is concluded that in vivo capillary permeability to protein is often increased in animals suffering from postirradiation thrombocytopenia. When this occurs, increased permeation of red cells from blood to lymph is also seen.

A review and Bayesian meta-analysis of clinical efficacy and adverse effects of 4 atypical neuroleptic drugs compared with haloperidol and placebo.

Aims: The objective of the study was to examine the efficacy and the degree of adverse effects connected with atypical neuroleptic drugs and haloperidol by using a previously described Bayesian statistical method that includes both direct and indirect comparisons simultaneously. Methods: The authors used the results of 30 double-blind, randomized studies including comparisons of 4 atypical neuroleptics and haloperidol, head-to-head or against placebo. We calculated the response ratios for drugs against placebo and thereafter the relative response ratios for one drug against another. With uniform priors, we calculated and ranked the posterior estimates of response ratios for antipsychotic effect, weight gain, and occurrence of extrapyramidal symptoms. Results: All second-generation neuroleptics analyzed are fairly effective with response ratios against placebo ranging between 1.55 (credibility interval, 1.36-1.76) and 1.99 (1.76-2.26), with clozapine being the most effective and aripiprazole the least effective among them. The risk of inducing weight gain is clearly very high for all 5 neuroleptic drugs compared with placebo with response ratios of 12.21 (10.22-15.05) for olanzapine and 11.28 (6.89-17.77) for clozapine. There is a clear increased risk of extrapyramidal adverse effects for haloperidol compared with placebo as the response ratio is 2.33 (2.03-2.49). The other drugs all have considerably less risk of extrapyramidal adverse effects. Conclusions: The 4 second-generation neuroleptics included in our meta-analysis show only small differences in overall efficacy, with clozapine being the most effective and aripiprazole the least effective among them. When the risk of adverse effects is analyzed, olanzapine and clozapine are afflicted with the highest risk of inducing weight gain and haloperidol with extrapyramidal symptoms. Even aripiprazole and risperidone, however, induce considerable weight gain compared with placebo but may be acceptable alternatives when tailoring drug treatment to the individual patient.

Does atenolol differ from other β-adrenergic blockers?

BackgroundA recent meta-analysis of drug effects in patients with hypertension claims that all β-adrenergic blockers are equally effective but less so than other antihypertensive drugs. Published comparisons of the β-adrenergic blocker atenolol and non-atenolol β-adrenergic blockers indicate different effects on death rates, arrhythmias, peripheral vascular resistance and prognosis post myocardial infarction, all in disfavour of atenolol. In keeping with these findings, the data presented in the meta-analysis indicate that atenolol is less effective than the non-atenolol β-adrenergic blockers both when compared with placebo and with other antihypertensive drugs. These findings were not, however, statistically significant.MethodsWe performed an additional analysis with a Bayesian statistical method in order to make further use of the published data.ResultsOur calculations on the clinical data in the meta-analysis showed 13% lower risk (risk ratio 0.87) of myocardial infarction among hypertensive patients taking non-atenolol β-adrenergic blockers than among hypertensive patients taking atenolol. The 90 % credibility interval ranged from 0.75 to 0.99, thereby indicating statistical significance. The probability of at least 10% lower risk (risk ratio ≤ 0.90), which could be considered to be of clinical interest, was 0.69.ConclusionTaken together with the other observations of differences in effects, we conclude that the claim that all β-adrenergic blockers are inferior drugs for hypertensive patients should be rejected. Atenolol is not representative of the β-adrenergic blocker class of drugs as a whole and is thus not a suitable drug for comparisons with other antihypertensive drugs in terms of effect. The non-atenolol β-adrenergic blockers should thus continue to be fundamental in antihypertensive drug treatments.

Shear stress activation of platelets with subsequent refractoriness.

Platelet rich plasma was prepared with soybean trypsin inhibitor (SBTI) as anticoagulant, to preserve normal Ca++-concentration, and subsequently tested in an aggregometer. Shear stress alone, induced by stirring, resulted in platelet aggregation and disaggregation. Such platelets showed only minor aggregational response on the addition of ADP, indicating that the platelets had been partly desensitized towards ADP-stimulation. When the stirrer was started at the same time as the addition of 1.6 microM ADP, the aggregation velocity was related to the speed of the stirrer. Disaggregation always started 1.5 min after the stimulus. Platelet shape change was apparently not influenced by the stirring. Since platelets from SBTI-anticoagulated blood could be aggregated by stirring alone, we examined the effect of centrifugation of whole blood at 50 xg for 3 and 10 min. Signs of transient aggregation and release of alpha-granule content were respectively observed.

Use of cardiovascular drugs after acute myocardial infarction: a marked shift towards evidence-based drug therapy.

AbstractObjective. To investigate the prescription pattern for cardiovascular drugs among patients discharged after an acute myocardial infarction (AMI) in hospitals that had participated in a corresponding study seven years earlier, and examine what the indications were for use of the different drugs. Methods. From 16 hospitals we drew a sample of patients who were discharged with a diagnosis of AMI during a three months period in 1999/2000. Physicians in each hospital obtained from the medical records the observed rate of use of cardiovascular drugs at discharge. The drug use was compared with findings from a corresponding sample drawn in 1993. The main indication for use of the different cardiovascular drugs was recorded for the 1999/2000 sample. Results. 399 patients discharged alive were included in the first study and 767 in the second. The use of beta-blockers, ACE inhibitors and statins rose substantially during the period. For patients aged ≤70 drug use in respectively 1993 and 1999/2000 was as follows: beta-blockers 73% vs 89%, ACE inhibitors 14% vs 29%, statins not recorded vs 82%; corresponding figures for patients aged >70 were: beta-blockers 45% vs 74%, ACE inhibitors 19% vs 38%, statins not recorded vs 35%. Aspirin/anticoagulant use was largely unchanged; 93% and 70% of patients aged ≤70 and >70 respectively used these drugs at the second survey. The use of regular nitrates and calcium antagonists had decreased. Nearly half of the >70 group and one-fifth of persons ≤70 used 5–9 cardiovascular drugs. Conclusion. At the end of the 1990s a substantial shift in drug therapy after AMI occurred, with a markedly increased use of drugs proven to be effective in clinical trials and less use of other cardiovascular drugs. The most frequently reported main indication for use of drugs was secondary prevention. The principles of evidence-based drug therapy became increasingly adopted among clinicians during the 1990s.

Common adverse events associated with an SSRI: meta-analysis of early paroxetine data.

We wanted to determine to what extent adverse drug effects associated with a selective serotonin reuptake inhibitor (SSRI) were known but not assessed before application for registration of paroxetine.

A 3-year survey quantifying the risk of dose escalation of benzodiazepines and congeners to identify risk factors to aid doctors to more rationale prescribing

Objectives This study investigated and quantified risk factors of dose escalation, as an indication of drug misuse and dependency of benzodiazepines and congeners, among presumably drug naïve patients in the Norwegian drug prescription database, observed over 3 years. Design Observational study. Setting Prescription database study. Participants We defined an excessive user as one redeeming more than two defined daily doses per day in 3 months. Primary and secondary outcome measures We examined the risk of excessive use over time and the effect of risk factors through multistate logistic regression and scenarios. Results Most of the 81 945 patients had zopiclone or zolpidem as the initial drug (63.8%), followed by diazepam (25.3%), oxazepam (6.1%), nitrazepam/flunitrazepam (2.9%), hydroxyzine/buspirone (1.6%) and alprazolam (0.3%). At any time 23% redeemed prescriptions, about 34% did not redeem any prescriptions beyond any 3-month period and 0.9% ended up as excessive users. Patients previously using drugs, such as opioids, antialcohol or smoke cessation treatment, had a higher risk to become excessive users compared to patients who had not. Patients whose first prescription was for oxazepam or nitrazepam/flunitrazepam had a higher risk of becoming an excessive user compared to those who started with diazepam. A specialist in general practice as the first-time prescriber was associated with a lower risk compared to doctors without specialty. Conclusions Most benzodiazepine use occurred according to guidelines. Still, some experienced dose escalation over time, and risk factors were previous use of other psychotropic drugs, long time use, choice of first-time drug and prescribers specialty. This could incite doctors to have a cessation plan when issuing first-time prescriptions.