WHO defined daily doses versus hospital-adjusted defined daily doses: impact on results of antibiotic use surveillance.

OBJECTIVES: To investigate effects on surveillance results of hospital antibiotic use when WHO defined daily doses (WHO DDDs) are adjusted to doses recommended for hospitalized patients [hospital-adjusted defined daily doses (haDDDs)]. METHODS: Data for antibiotic use in 2006-11 for all 22 Norwegian Health Enterprises were analysed with both WHO DDDs and haDDDs as numerators. The haDDDs were determined from recommendations given in regional and national guidelines on antibiotic use in hospitals. The two ways of calculating the amount of antibiotic use were compared, with either the number of bed days (BDs) or the number of discharges as the denominator. The drug utilization 90% methodology was applied for ranking the use of the various antibiotics. RESULTS: DDD adjustments altered the figures for total antibiotic use from 67.1 WHO DDDs/100 BDs to 49.3 haDDDs/100 BDs (-26.4%). The most marked difference was found for penicillins: 31.1 WHO DDDs/100 BDs versus 13.4 haDDDs/100 BDs (-56.8%). The corresponding figures for broad-spectrum antibiotics were 17.3 and 15.5 (-10.4%), respectively; for these antibiotics, the conversion changes varied significantly between institutions, from -16.7% to -3.3%. Ranking antibiotic use based on haDDDs resulted in higher positions for metronidazole, cefuroxime, cefotaxime and cefalotin/cefalexin compared with the WHO DDD-based ranking, where the penicillins dominated. CONCLUSIONS: The low-set WHO DDDs for penicillins caused skewed surveillance results that concealed the real magnitude of broad-spectrum antibiotic use and distorted interhospital comparisons. For surveillance of antibiotic use in hospitals, WHO DDDs should be supplemented with haDDDs.

New anticoagulants as thromboprophylaxis after total hip or knee replacement.

OBJECTIVES: Due to a high risk of thromboembolism in patients undergoing major orthopedic surgery, it has become standard practice to give thromboprophylactic treatment. We assessed the relative efficacy and cost-effectiveness of two new oral anticoagulants, rivaroxaban and dabigatran, relative to subcutaneous enoxaparin for the prevention of thromboembolism after total hip replacement (THR) and total knee replacement surgery (TKR). METHODS: We conducted a systematic review of the literature to assess efficacy and safety, and evaluated quality of documentation using GRADE. Cost-effectiveness was assessed by developing a decision model. The model combined two modules; a decision tree for the short-term prophylaxis and a Markov model for the long-term complications and survival gain. RESULTS: For rivaroxaban compared with enoxaparin, we found statistically significant decreases in deep vein thrombosis, but also a trend toward increased risk of major bleeding. For mortality and pulmonary embolism there were no statistically significant differences between the treatments. We did not find statistically significant differences between dabigatran and enoxaparin for our efficacy and safety outcomes. Assuming a willingness to pay of EUR62,500 per QALY, rivaroxaban following THR had a probability of 38 percent, and enoxaparin following TKR had a probability of 34 percent of being cost-effective. Clinical efficacy had the greatest impact on decision uncertainty. CONCLUSIONS: Dabigatran and rivaroxaban are comparable with enoxaparin following THR and TKR regarding the efficacy and safety outcomes. However, there is great uncertainty regarding which strategy is the most cost-effective. More research on clinical efficacy of rivaroxaban and dabigatran is likely to change our results.

Choice of initial antihypertensive drugs and persistence of drug use--a 4-year follow-up of 78,453 incident users.

PURPOSE: To investigate patterns of initial drug therapy for the treatment of hypertension and to evaluate treatment persistence and change of treatment during a 4-year period in patients receiving thiazides (TZs) and/or angiotensin II-receptor blockers (ARBs) as first-line treatment. METHODS: All initial users of antihypertensive drugs in 2005 and 2009 registered in the Norwegian Prescription Database were included. Treatment on five index dates at 1-year intervals was recorded. A patient was considered to be under treatment on an index date if a drug had been dispensed within the previous 180 days and to have maintained treatment persistence if he/she was on any antihypertensive treatment on the index date and all previous index dates. RESULTS: Among 78,453 new users of antihypertensives in 2005, women started more often with TZs than men (30 vs. 25 %) and less often with ARBs (22 vs. 25 %). In men, the hazard of non-persistence with antihypertensive treatment was significantly lower among initial ARB users than among TZ users (hazard ratio 0.87, 95 % confidence interval 0.81-0.94); in women no significant difference was found. After 4 years, 49 % of the men and 51 % of the women who had started with plain TZs were still using TZs, whereas 65 % of the male ARB users and 60 % of the female ARB users were still using ARBs. CONCLUSION: TZs and ARBs were the most widely used first-line antihypertensives. Among the men enrolled in the study, ARB users had a somewhat better persistence with antihypertensive treatment than TZ users. Among both genders, continuation on ARBs was more common than continuation on TZs.

[Patterns in the prescription of antihypertensive drugs in Norway, 1975-2010]. / Forskrivning av antihypertensive legemidler 1975-2010.

BACKGROUND: A complete overview of drugs used for hypertension is not available from official data sources. The aim of this study was to investigate the use of blood pressure medication over the years to identify trends in consumption patterns. MATERIAL AND METHOD: Data were collected from the Norwegian drug wholesaler statistics for the years 1975-2010 and from the Norwegian prescription database 2004-2010. Defined daily doses (DDD) per 1000 inhabitants per day, number of users and prevalence by gender and age were analysed. RESULTS: In the period 1975 to 2010 the use of antihypertensives increased from 55 to 248 DDD/1000 inhabitants/day (Norwegian drug wholesaler statistics). Data from the Norwegian prescription database show that in 2010 there were a total of 754 909 users of antihypertensives, of whom 638 830 had received the diagnosis hypertension. Thiazides and angiotensin II antagonists had the greatest increase in number of users from 2004 to 2010. In all ages up to 73 years, a higher proportion of men were prescribed drugs for hypertension in 2010, whereas in the over-73 s these drugs were most widely used by women. INTERPRETATION: The use of antihypertensives is steadily increasing. Angiotensin II antagonists and thiazides are the most commonly used drugs. The authorities'' decision in 2004 that thiazides should be regarded as first-line therapy for hypertension probably contributed to increased use of thiazides.

Increased antibiotic use in Norwegian hospitals despite a low antibiotic resistance rate.

OBJECTIVES: Although antibiotic use and resistance are low in Norway, the situation risks changing for the worse. We investigated trends in antibiotic use and assessed them in relation to antibiotic resistance in Norway. METHODS: We drew on hospital pharmacy sales data to record antibiotic use from 2002 to 2007 in eight hospitals serving 36% of the nation's population. Antibiotic use was measured using different indices with defined daily doses (DDDs) as the numerator (WHO ATC/DDD classification). RESULTS: Total antibiotic use increased from 1.02 to 1.30 DDDs/1000 inhabitants/day (DIDs) and from 61.7 to 72.4 DDDs/100 bed-days (BDs) (17.4%); related to the number of discharges, no significant DDD change was shown. Their use in core units (adult intensive care units, recovery/post-operative wards and departments of internal medicine and surgery with all subspecialties) increased from 64.1 to 80.8 DDDs/100 BDs (26.1%) and by 3.1% related to the number of discharges. The total use of broad-spectrum antibiotics increased by 47.9% when measured as DDDs/100 BDs, and by 19.1% based on the number of discharges; the corresponding figures for core units were 60.5% and 31.2%, respectively. CONCLUSIONS: There was a substantial increase in total antibiotic use, and an even more pronounced increase in the use of broad-spectrum antibiotics, which seems unjustified considering the current low antibiotic resistance in Norway.

Pharmacy sales data versus ward stock accounting for the surveillance of broad-spectrum antibiotic use in hospitals.

BACKGROUND: Antibiotic consumption in hospitals is commonly measured using the accumulated amount of drugs delivered from the pharmacy to ward held stocks. The reliability of this method, particularly the impact of the length of the registration periods, has not been evaluated and such evaluation was aim of the study. METHODS: During 26 weeks, we performed a weekly ward stock count of use of broad-spectrum antibiotics--that is second- and third-generation cephalosporins, carbapenems, and quinolones--in five hospital wards and compared the data with corresponding pharmacy sales figures during the same period. Defined daily doses (DDDs) for antibiotics were used as measurement units (WHO ATC/DDD classification). Consumption figures obtained with the two methods for different registration intervals were compared by use of intraclass correlation analysis and Bland-Altman statistics. RESULTS: Broad-spectrum antibiotics accounted for a quarter to one-fifth of all systemic antibiotics (ATC group J01) used in the hospital and varied between wards, from 12.8 DDDs per 100 bed days in a urological ward to 24.5 DDDs in a pulmonary diseases ward. For the entire study period of 26 weeks, the pharmacy and ward defined daily doses figures for all broad-spectrum antibiotics differed only by 0.2%; however, for single wards deviations varied from -4.3% to 6.9%. The intraclass correlation coefficient, pharmacy versus ward data, increased from 0.78 to 0.94 for parenteral broad-spectrum antibiotics with increasing registration periods (1-4 weeks), whereas the corresponding figures for oral broad-spectrum antibiotics (ciprofloxacin) were from 0.46 to 0.74. For all broad-spectrum antibiotics and for parenteral antibiotics, limits of agreement between the two methods showed, according to Bland-Altman statistics, a deviation of ± 5% or less from average mean DDDs at 3- and 4-weeks registration intervals. Corresponding deviation for oral antibiotics was ± 21% at a 4-weeks interval. CONCLUSIONS: There is a need for caution in interpreting pharmacy sales data aggregated over short registration intervals, especially so for oral formulations. Even a one-month registration period may be too short.

Changes in myocardial infarction mortality.

BACKGROUND: The incidence of myocardial infarction (MI) in Norway has decreased substantially over the last two decades, according to recent publications based on data from the Norwegian Patient Registry. To better understand the development of cardiovascular disease over time we have investigated the development of MI mortality in light of the decrease in MI incidence. MATERIAL AND METHODS: Data on MI mortality were retrieved from the Cause of Death Registry (Statistics Norway) for the period 1969-2007 and analyzed. Mortality rates (death per 100,000 inhabitants) were calculated for the total population according to sex and the following age groups: 0-39 years, 10-year groups in the range 40-79 years and 80 years and higher. RESULTS: Total MI mortality showed a weak increase in the 1970s and the 1980s until 1987. Mortality decreased substantially from 1987 to 2007, 64% for men and 47% for women. The reduction in mortality started first for the youngest age groups. In 2007, the decrease in mortality from the peak years was about 70% for the age groups below 80 years and about 40% in the group above 80 years of age. INTERPRETATION: After small changes in the 1970s and 1980s, MI mortality has decreased steadily in the 1990 s in all age groups and has continued to do so after 2000.

[Acute myocardial infarctions in Norway 1991 - 2007]. / Hjerteinfarkt i Norge 1991 - 2007.

BACKGROUND: The objective of the study was to analyse the number of AMI (acute myocardial infarctions) registered in the period 1991 - 2007, with special emphasis on the development after 1999, and with this background discuss changes in incidence. MATERIAL AND METHODS: We analysed data from NPR (the Norwegian Patient Register), on patients discharged from hospitals in the period 1991 - 2007 with the main diagnosis AMI. For the year 2004, a patient-based dataset was made available from SINTEF Health Research/NPR. The time for when troponin assays (for diagnosing AMI) were implemented in Norwegian hospitals was recorded through a questionnaire survey. RESULTS: The number of discharges for these patients decreased during the 90 s. From 2000 to 2007, the total number of discharges increased considerably (from 11,892 to 19,757 [66 %]). In patients below 80 years of age the number of discharges per 100,000 inhabitants was 283 in 1991 and 196 in 1999. After controlling for patient transfers between hospitals and introduction of troponins for diagnosing of AMI, the number of patients below 80 years admitted to hospital in 2004 was estimated to 142 - 162 per 100,000 inhabitants. INTERPRETATION: The trend for a decrease in AMI incidence seems to have continued from the 1990 s to after 2000 for the age groups below 80.

Sex-based differences in premature first myocardial infarction caused by smoking: twice as many years lost by women as by men.

BACKGROUND: It has been debated whether smoking increases the risk of heart disease relatively more in women than in men. It is not known whether there are sex differences with regard to how many years prematurely smoking causes acute myocardial infarction (AMI) to occur. We aimed to determine how smoking affects the age of onset of first myocardial infarction in both the sexes. DESIGN: Clinical data were consecutively entered into a database and were analysed with a multivariate regression technique. METHODS: In the years 1998-2005, data on 1784 consecutive patients (38.3% women) who were discharged from or died in a district general hospital with a diagnosis of first myocardial infarction were included in the study. Age at first AMI was analysed. RESULTS: Unadjusted mean ages were 76.2 years for women and 69.8 years for men, a difference of 6.4 years (P<0.001). Mean age within the various groups was: women nonsmokers 80.7 years, women smokers 66.2 years, difference 14.4 years (P<0.001); men nonsmokers 72.2 years, men smokers 63.9 years, difference 8.3 years (P<0.001). After adjustment for risk factors (hypertension, cholesterol levels, diabetes) and patient characteristics (history of angina, history of stroke) 13.7 years of the age difference in women were attributed to smoking; the corresponding figure in men was 6.2 years (P<0.001). CONCLUSION: First AMI occurred significantly more prematurely in women than in men smokers, implying that twice as many years were lost by women as by men smokers.

[Calcium antagonists in treatment of hypertension]. / Kalsiumantagonister ved høyt blodtrykk.

A sizeable number of antihypertensive drugs from different drug classes have received market authorization. New results from clinical studies are steadily launched, and this is also the case for calcium antagonists, which were established as antihypertensive drugs already in the 1970s. Which place do calcium antagonists have in the present treatment of hypertension?

[Effects of antihypertensive drugs on glucose metabolism and cardiovascular events]. / Effekter av antihypertensiver på glukosemetabolisme og kardiovaskulaere hendelser.

BACKGROUND: Diuretics and beta-blockers (conventional antihypertensive therapy) may increase the level of blood glucose. Such an increase could enhance the risk of cardiovascular events and have an unfavourable effect on prognosis, but available documentation is not conclusive. MATERIAL AND METHOD: The material consists of literature collected over many years, supplemented with literature retrieved through an extensive search (non-systematic) in Pubmed. RESULTS: Several studies, of 4-6 years duration, have shown that conventional therapy induces a small increase of blood glucose without increasing cardiovascular events. Newer antihypertensive drugs (angiotensin converting enzyme (ACE) inhibitors, angiotensin II (AII)- receptor blockers and calcium blockers) do not have this effect. Conventional therapy can also prevent cardiovascular events in patients with diabetes. Several studies on hypertension have shown that drugs' ability to reduce blood pressure is most decisive for their prevention of events. INTERPRETATION: In most cases, diuretics and beta-blockers are as effective as the newer antihypertensives, but drugs with an effect on the renin-angiotensin system are usually preferred as first choice in patients with diabetes. However, when several drugs must be combined in order to achieve the blood pressure goal in diabetic patients (< 130/80 mm Hg), diuretics and beta-blockers may be administered.

[Cholinesterase inhibitors in the treatment of dementia--are they useful in clinical practice?]. / Kolinesterasehemmere mot demens--nyttig i klinisk praksis?

BACKGROUND: Some randomized studies, mostly of short duration, have indicated that cholinesterase inhibitors (donepezil, rivastigmine and galantamine) may have a beneficial effect in Alzheimer's disease, vascular dementia and in dementia caused by Lewy body disease. The benefit of these drugs in clinical practice has not been satisfactorily documented. MATERIAL AND METHOD: Literature collected regularly for many years supplemented by extensive non-systematic searches of Pubmed and Embase. RESULTS: Only in a few placebo-controlled, double-blind, randomised studies were the patients followed for more than one year. Several clinical tests were performed, among them the Mini Mental Status (MMS)-test, which is the most commonly used test in clinical practice. The three cholinesterase inhibitors led to statistically significant results, although of limited clinical relevance, in various forms of dementia. INTERPRETATION: Based on the results obtained it could be questioned whether the observed effects are of clinical significance. Only a small proportion of patients with Alzheimer's disease seem to benefit from the cholinesterase inhibitors tested, and it is difficult to predict who will in advance. Treatment should first be evaluated after 2-4 months and subsequently on a regular basis, and accepted clinical tests should be applied.

[Can cardiovascular events be prevented by raising HDL cholesterol?]. / Kan økning av HDL-kolesterolnivået forebygge hjerte- og karsykdom?

BACKGROUND: Low HDL cholesterol is a risk factor for development of atherosclerotic disease. The possibility of increasing HDL cholesterol levels to prevent cardiovascular disease is an issue of great interest. MATERIAL AND METHODS: Literature was retrieved from Pubmed and Embase and relevant literature and reference lists were reviewed. RESULTS: Physical exercise, smoking cessation, weight control and moderate alcohol intake has been shown to increase HDL cholesterol levels. Of today's available drugs, Niacin has the greatest HDL cholesterol-enhancing effect, but clinical effects have not been adequately documented. Fibrates increase HDL cholesterol, but it has not been documented that this results in clinical benefit. Statins increase HDL cholesterol moderately, but it is not clear whether such increase has been crucial for the reduction of cardiovascular events in the large statin trials. Combinations of various lipid-lowering agents can increase HDL cholesterol additively, but clinical benefit has not been proven. Inhibition of cholesterol ester transfer protein with torcetrapib raised HDL cholesterol markedly, but increased the risk of death and cardiovascular events. Infusion of a apolipoprotein A-I Milano/phospholipid complex was associated with regression of coronary atherosclerosis. New HDL-modifying therapies are under investigation. INTERPRETATION: HDL cholesterol can be used for assessment of cardiovascular risk, but it has not been documented that drug-induced enhancement of HDL cholesterol can reduce the occurrence of cardiovascular events.

[Clinical use of COX inhibitors--a consensus]. / Klinisk bruk av COX-hemmere--en konsensus.

BACKGROUND: Many physicians have been uncertain about treatment options following reports that linked cyclooxygenase (COX) inhibitors to serious cardiovascular events and the subsequent withdrawal of two selective COX-2 inhibitors. Therefore, on June 14, 2005, the Norwegian Medicines Agency and the Department of Pharmacotherapeutics, University of Oslo, held an expert meeting on COX inhibitors. METHODS: Presentations and discussions based on existing literature and statements from European (EMEA) and American (FDA) medicine authorities. This constitutes the basis for the current recommendations. RESULTS AND INTERPRETATION: COX inhibitors have solely symptomatic effects, and there are no differences in analgesic and anti-inflammatory efficacy between the various COX-inhibitors. These drugs should, if possible, be used at the lowest effective dose and for as short a time as possible. Some of the COX-2 selective inhibitors show a lower incidence of gastrointestinal side effects than unselective COX inhibitors, but this advantage can be outweighed by increased occurrence of cardiovascular side effects. Generally, the cardiovascular adverse effects are more serious, and more often irreversible, than the gastrointestinal adverse effects. Patients with established or increased risk of cardiovascular disease should not use COX-2-selective inhibitors. In general, COX inhibitors should, if possible, not be administered to individuals with previous peptic ulcer disease, hypertension, heart failure, or kidney disease. There is a need for more data on the effect and safety of COX inhibitors.

[Do vitamins C and E protect against the development of carotid stenosis and cardiovascular disease?]. / Beskytter vitamin C og E mot utvikling av carotisstenose og kardiovaskulaere sykdommer?

BACKGROUND: Some observational and randomized, clinical interventional studies have indicated that the antioxidative vitamins C (ascorbic acid) and E (alpha-tocopherol) can reduce intima-media thickness of the carotid arteries. It is, however, not clarified whether these vitamins may have a preventive effect against cardiovascular events. MATERIAL AND METHODS: The literature on the effects in relation to several cardiovascular endpoints of vitamins C and E, also used in combination, has been evaluated. The literature has been continuously and systematically collected over many years and supplemented by recent studies retrieved from Medline. RESULTS: Observational studies including mainly healthy individuals have shown a favourable relationship between intake of vitamins C and E, also taken in combination, and subsequent cardiovascular events. However, most randomized, clinical interventional studies including patients with manifest atherosclerotic disease have not been able to document such a relationship. INTERPRETATION: The discrepancy found between observational studies and clinical interventional studies may be due to different study populations (healthy/ill individuals) and differences regarding age, sex, diet, smoking, degree of oxidative stress and other probable confounding factors. The significance of vitamins C and E in preventing cardiovascular disease is in our opinion not yet clarified.

[ACE inhibitor or ATII receptor blocker in heart failure and myocardial infarction?]. / ACE-hemmer eller AII-reseptorblokker ved hjertesvikt og hjerteinfarkt?

Angiotensin converting enzyme (ACE) inhibitors are important drugs in the treatment of hypertension, heart failure and after acute myocardial infarction. The patents for most of these agents have now expired and the industry has introduced angiotensin II receptor blockers (ATII receptor blockers) with a mode of action similar to that of ACE inhibitors. All six ATII receptor blockers on the Norwegian market have the indication hypertension, while one of them also has the indication heart failure when treatment with ACE inhibitors is not appropriate. Some studies have compared ACE inhibitors with ATII receptor blockers in the treatment of heart failure and after acute myocardial infarction and found the two classes of drugs to be about equally efficacious. There is no reason to change the current practice of choosing ACE inhibitors as first line treatment for these conditions. If ACE inhibitors cannot be used, ATII receptor blockers represent an acceptable alternative.