KAUNAS UNIVERSITY OF MEDICINE FACULTY OF PHARMACY
DEPARTMENT OF BASIC AND CLINICAL PHARMACOLOGY
Pharmacoeconomical / pharmacoepidemiological evaluation of medicines utilization in hkum from 2001 to 2005 MASTER WORK (Pharmacoepidemiology) Supervised by: Doc.dr. E.Kaduševičius Performed by: Gabrielė Kildonavičiūtė Faculty of Pharmacy 5/2 gr. Kaunas, 2006
TABLE OF CONTENTS
ABBREVIATIONS………4
1. INTRODUCTION………..5
2. BACKGROUND………7
2.1 Hospital of Kaunas University of Medicine...7
2.2 Aims of Pramacoeconomical analysis...7
2.3 Aims of Pharmacoepidemiological analysis...8
2.4 Reasons of the irrational use of medicines...9
2.5 Evaluation of medicines consumption in hospitals……….………...…...10
2.6 Evaluation of LMWH versus UFH...13
3. OBJECTIVE……….……….19
4. AIMS………..19
5. METHODOLOGY……….20
5.1 The purpose of ATC/DDD system...20
5.2 The ATC classification – structure and principles………..20
5.3 The DDD – definition and principles...………21
5.4 Drug utilization……….………...22
5.5 Definition of cost-minimization analysis……….23
5.6 Reference pricing……….24 5.7 Meta-analysis methodology...………...25 6. RESULTS………...27 7. DISCUSSION………...56 8. CONCLUSIONS……….……...61 SUMMARY ………..……….……....….62 SANTRAUKA……...……….……...63 REFERENCES……...……….……….……....64 ANNEX 1 - 17………...…..68 - 87
ABBREVIATIONS
ACS Acute Coronary Syndrome
ATC Anatomical Therapeutic Chemical classification CEF Cefalosporins
CI Confidence Interval DDD Defined daily dose
DVT Deep venous thromboembolism HD Hospitalization days
HKUM Hospital of Kaunas University of Medicine ICU Intensive Care Unit
IDS Infectious disease specialist
LMWH Low-molecular-weight heparin MACE Major cardiac events
MCID Minimally clinically important difference MERO Meropenem
MI Myocardial Infarction PD Patient-days
PE Pulmonary embolism PPP Pharmacy purchased price PTAZ Piperacillin-Tazobactam
UCAD Unstable Coronary Artery Disease UFH Unfractionated heparin
VT Venous thromboembolism WHO World Health Organization
1. INTRODUCTION
The innovation and diffusion of new technologies is in large measure responsible for the persistent rise in the cost of health care. The general aim of health economic evaluation is to prioritize health care so as to maximize population health from available health care resources. [1] Expenses for medicinal products account for a large part of the total expenses within the health area. One must contribute to a rational use of the money so that one can afford to utilize new and effective medicinal products. In other words, everyone should attempt to ensure the best foundation possible for rational pharmacotherapy. [2]
Rational drug therapy means the use of right medicine in the right manner (dose, route and frequency of administration, duration of therapy etc.) in right patient at a right cost. Rational drug therapy also means using the drug when necessary. Hence, the drug chosen for a patient should be effective, safe and acceptable quality and cost. [3]
First important reason why the consumption and sales of medicines are increasing is the transition to new and often more expensive medicines, which are potentially more efficacious and/or exhibit less adverse drug reactions. In Norway innovative medicines represent more than 40 percent of the total sales of medicines, as measured by the pharmacy purchase price (PPP).
Secondly, as the population as a whole is growing older, there is an increasing need for medicines.
A third reason for the increase is the advent of new medicines, which have made treatment possible for patients who previously had insufficient possibilities for medical treatment. The increase may also be related to an increased consensus across national borders on the treatment of various disorders. [4]
Medicines form a crucial part of the treatment of most, if not all, patients. The clinical and cost effective use of medicines is important in meeting the needs of individual patients. It finds that medicines use is not always optimized, leading to poorer quality and higher costs. "Medication errors occur too often and their effect on patients and National Health-care Systems costs can be profound." It sees managing the ways that medicines are used in hospitals as the "business of all clinical staff". Medicines management is a strategic issue fundamental to the way that hospitals work, to the quality of patient care and their improving health. [5]
Almost half of all medicines globally are used irrationally. This, say medicines experts at the World Health Organization (WHO), can have severe consequences: adverse drug reactions, drug resistance, protracted illness and even death. In addition, the financial cost incurred by individuals and governments due to irrational use is unnecessary and often extremely high. [6]
Irrational use of medicines is a major problem worldwide. Any selection of medicines therefore needs to take account of public health relevance, the best available clinical evidence of efficacy and safety as well as an assessment of comparative cost-effectiveness. The process needs to be transparent and should consider the perspectives of the patient, health professionals and national authorities. [7]
Medically inappropriate, ineffective, and economically inefficient use of pharmaceuticals is commonly observed in the health care system throughout the world. This problem will usually come to the attention of health decision makers or managers when there is an acute shortage of pharmaceutical budget and action for cost efficiency is required. The need for promoting appropriate use of drugs in the health care system is not only because of the financial reasons with which policy makers and managers are usually most concerned. Appropriate use of drugs is also one essential element in achieving quality of health and medical care for patients and the community. [8]
Relevance and novelty of this work
The pharmacoeconomical and pharmacoepidemiological drug consumption analysis has been performed in one of the biggest health-care provider – Hospital of Kaunas University of Medicine (HKUM). The evaluations involve the estimations of the five year period from 2001 to 2005.
Drugs have become the fastest-rising component of health care costs, with expenditures on medications set to outstrip hospital costs in many health care systems as the single most expensive aspect of medical care. [9]
According to the available literature, the comprehensive pharmacoepidemiological and pharmacoeconomical analysis of medicines consumption in hospitals has not been performed in Lithuania jet. So this work could be named as the first one, evaluating drug utilization from both – pharmacoeconomical and pharmacoepidemiological points of view.
Hospitals, and especially big University Institutions, every year consume big amounts of the Health-care finances. So it is really topical to accomplish a comprehensive analysis of the consumed medicines for financial and non-financial reasons.
The fulfilled drug consumption analysis is a new thing in our country. After the performed search for the similar information, it became obvious that such estimations were not part of the every-day work in Lithuanian health-care establishments. In the mentioned analysis the drug consumption data was taken from the year 2001 – 2005, so the results are topical, confident and up-to-date.
The performed estimations are topical because:
o Drug expenses are increasing dramatically, every year they consume a big part of total health care costs.
o The rational consumption of medicines and the proper usage of money are becoming more important every year.
o Confident calculations should be performed every year in order to control the increasing drug expenses.
o Such analysis should lead to implementation if different guidelines about the rational utilization of medicines.
2. BACKGROUND
2.1. Hospital of Kaunas University of Medicine
Hospital of Kaunas University of Medicine (HKUM) is the largest medical institution in Lithuania, providing specialized best quality services of medical care for people from Kaunas and from all over Lithuania. More than 1000 physicians and more than 2000 nursing specialists are employed there. In HKUM 2200 patients can be hospitalized at the same time. Besides, in the year 2004 more than 71 thousand people were admitted to the mentioned hospital. [10]
2.2. Aims of pharmacoeconomical analysis
Pharmacoeconomics is a relatively new branch of health economics. Economics is about how we, individuals, society and governments, choose to use fixed resources. Fixed resources can be, for example, time, effort, money, machinery or buildings. Currently, the demand for health care cannot be met with the resources individuals, society and governments are prepared to allocate to it.
Pharmacoeconomics helps us to make decisions about the use of medicines. Most pharmacoeconomic studies in health care are cost-effectiveness studies set out to demonstrate how to achieve an objective with the least use of resources. This should not be confused with efficiency, which measures how well we use resources in order to obtain the desired outcome. Other types of pharmacoeconomic analyses are cost minimisation analyses, where two or more interventions having identical outcomes are evaluated for the least cost for that outcome; cost utility analyses, where the outcome is measured as a utility, such as quality of life; and cost-benefit analyses, which involve the measurement of both tangible and intangible values. Cost-benefit studies are difficult to design and the biggest problem is quantifying benefits in financial terms. They are therefore rarely used in a health care setting.
Pharmacoeconomics is used at all stages in the development of medicines by the pharmaceutical industry, when medicines are researched, produced and marketed. Some countries insist on pharmacoeconomic evaluations as part of the licensing process. Most hospital pharmacists use pharmacoeconomics to assist with making decisions involving formularies and how medicines can be used in a more cost-effective or cost-beneficial manner.[11]
2.3. Aims of phamacoepidemiological analysis
Pharmacoepidemiology may be defined as the study of the utilization and effects of drugs in large numbers of people. To accomplish this study, pharmacoepidemiology borrows from both pharmacology and epidemiology. Thus, pharmacoepidemiology can be called a bridge science spanning both pharmacology and epidemiology. Pharmacology is the study of the effect of drugs and clinical pharmacology is the study of effect of drugs in humans. Part of the task of clinical pharmacology is to provide a risk benefit assessment for the effect of drugs in patients. Doing the studies it is needed to provide an estimate of the probability of beneficial effects in populations, or the probability of adverse effects in populations and other parameters relating to drug use may benefit from using epidemiological methodology. Pharmacoepidemiology then can also be defined as the application of epidemiological methods to pharmacological issues.
Epidemiology can be defined as the study of the distribution and determinants of diseases in populations. Epidemiological studies can be divided into two main types: 1. Descriptive epidemiology describes disease and/or exposure and may consist of calculating rates, e.g., incidence and prevalence. Such descriptive studies do not use control groups and can only generate hypotheses, but not test them. Studies of drug utilization would generally fall under descriptive studies. 2. Analytic epidemiology includes two types of studies: observational studies, such as case-control and cohort studies, and experimental studies which would include clinical trials such as randomised clinical trials. The analytic studies compare an exposed group with a control group and are usually designed as hypothesis testing studies. [12]
Pharmacoepidemiologic methods are increasingly being used to evaluate the total costs associated with drug therapy. These studies include evaluation of the overall effects of medicines on the utilization of medical services and costs of total medical care. The rates and costs of beneficial and adverse drug effects may be quantified, including resource costs such as medication acquisition and administration. Such methods can be utilized to compare the cost effectiveness of two or more alternative therapies which have different ingredients costs and differ in efficacy. [13]
2.4 Reasons of the irrational use of medicines
There are many different factors which affect the irrational use of drugs. In addition, different cultures view drugs in different ways, and this can affect the way drugs are used.
The major forces can be categorized as those deriving from patients, pre-scribers, the workplace, the supply system including industry influences, regulation, drug information and misinformation, and combinations of these factors. [8]
Table 1. The reasons of the irrational use of drugs.
Patients - drug misinformation misleading beliefs patient demands/expectations Pre-scribers - lack of education and
training
inappropriate role models lack of objective drug information generalization of limited experience misleading beliefs about drugs efficacy Workplace - heavy patient load pressure to prescribe
lack of adequate lab capacity insufficient staffing Drug Supply System - unreliable
suppliers
drug shortages expired drugs supplied Drug Regulation - non-essential drugs
available
non-formal pre-scribers lack of regulation enforcement Industry - promotional activities misleading claims
The impact of this irrational use of drugs can be seen in many ways:
Reduction in the quality of drug therapy leading to increased morbidity and mortality, Waste of resources leading to reduced availability of other vital drugs and increased costs,
Increased risk of unwanted affects such as adverse drug reactions and the emergence of drug resistance.
Psychosocial impacts, such as when patients come to believe that there is "a pill for every ill". This may cause an apparent increased demand for drugs. [8]
2.5. Evaluation of medicines consumption in hospitals
The importance of rational antibiotic policy is unquestionable both from financial and professional point of view. Surgery related antibiotic use is one of most important issues. [14]
Pharmaceutical costs reduction is one of the main objectives in the Public Health System. Hospital Pharmacy Department has an important role in this field. The example was recorded in hospital in Girona, Spain. There the consumption of antimicrobials in ICU was expressed as DDD per 100 hospital stays (DDD/100 S). Total use of antibiotics has grown from 235.01 in 2002 to 265.85 DDD/100S in 2003. Cost of antimicrobial therapy from 1997 to 2002 experimented minimal variation (medium 80878.53 euro; SD=1290). Increase from 2002 to 2003 was 45.24% (respectively cost 82032.04 euro, 119150.49 euro). About 45.42% increase the new antimicrobials represent. [15].
As antimicrobials are a therapeutical group with the major impact on public health, it is essential to optimize their use. It is well known that the same antimicrobials should not be used simultaneously in surgical prophylaxis and in treatment of infections to avoid resistance emergence that may compromise infection control. The guidelines established cefazolin and cefoxitin as antimicrobials of choice for surgical prophylaxis an gave pharmacists the authority to refuse their use out of the operating room. Design: two year (2001, 2003) retrospective study comparing antimicrobial consumption before and after guidelines approval on antimicrobial use in surgical prophylaxis. DDD/100 beds (%DDD) and DDD/100 surgeries (%DDD) were the main outcomes measured. As a result, surgical wards had significant reduction in the use of 1st (%DDD 2001: 4.96;
2003: 2.16) and 2nd generation cephalosporins (%DDD 2001: 10.65; %DDD 2003: 0.53). Cefazolin %DDD 2001: 4.45; 2003: 0.02. Cefoxitin %DDD 2001: 10.42; 2003: 0.06. An increase of the use of the third generation cephalosporins was also observed, namely ceftriaxone (%DDD 2001: 0.99; 2003: 4.6), aminopenicillins, ureidopenicillins and carbapenems. The analysis of operating rooms antimicrobial consumption showed an increase in the use of cefazolin and cefoxitin, although they were already the most used antimicrobials in 2001. Cefazolin %DDDS 2001: 43.84; 2003: 55.76. Cefoxitin %DDDS 2001: 17.48; 2003: 25.05. [16].
Inappropriate use of antibiotics results in increasing resistance to antibiotic drugs and escalating hospital costs. Antibiotic utilization was expressed as the number of DDDs per 1000 patient-days (PD) and as the number of DDDs per patient-days per EUR. In University Hospital, Yugoslavia, prior overall drug use was 3422 DDD/1000PD and 1691DDD/1000PD/EUR. After implementation of Quality measures the overall drug use was 2379DDD/1000PD (30% decrease) and 925DDD/1000PD/EUR (45% decrease). The overall use of antibiotics prior to implementation was 666DDD/1000PD and 776DDD/1000PD/EUR . After implementation the overall use of antibiotics was 493DDD/1000PD (26% decrease) and 524DDD/1000PD/EUR (32% decrease). The use of cephalosporins III generation significantly decreased from 57DDD/1000PD before, to 30DDD/1000PD after implementation Quality measures in Medicines Management i.e. decreased by 47% and in cost value from 498DDD/1000PD/EUR before to 279DDD/1000PD/EUR after implementation i.e. decreased by 44%. [17]
There is evidence that in Serbia’s hospitals drug utilization (consumption and costs) is not rational. The study analyzed the influence of implementation of Quality measures in Medicines Management on drug utilization in general hospital in Jagodina, Serbia (the year 2002-1004). Drug utilization was expressed as the number of DDDs per 1000 patient-days (PD) and as the number of DDDs per 1000 patient-days per EUR. Prior to implementation Quality measures in Medicines Management the overall drug use was 7333 DDD/1000PD and 2318DDD/1000PD/EUR. After implementation of Quality measures the overall drug use was 5475DDD/1000PD (25% decrease) and 2207DDD/1000PD/EUR (5% decrease). The analysis showed decrease in the total budget spent on antibiotics (from 45% prior to the implementation to 39% after it). The overall use of antibiotics prior to implementation was 552 DDD/1000PD (decrease 15%) and 732 DDD/1000PD/EUR (decrease 39%). There has been a significant change in the type of antibiotics prescribed, as well as in the percentage of the total budget spent on certain antibiotic. The use of cephalosporins III generation decreased from 67 DDD/1000PD before to 43 DDD/1000PD after implementation Quality measures in Medicines Management i.e. decreased by 36% and in cost value from 586 DDD/1000PD/EUR before to 355 DDD/1000PD/EUR after implementation i.e. decreased by 40%. [18].
Piperacillin-tazobactam (PTAZ) was introduced to replace piperacillin and to avoid a consecutive increase in the use of meropenem (MERO) and cephalosporin sod 3rd and 4th generation (CEF). Erasme hospital in Brussels, Belgium, is a university hospital with the infectious diseases’ specialists (IDS) consulting team, a 20-year experience of local guidelines of antimicrobial use. During the observation, PTAZ was ordered 150 times. A significant increase in use was observed with a monthly amount of 15 and 31 orders in November 2002 and May 2003, respectively (P linear trend < 0.05). The total amount of the broad spectrum patient-days expressed in defined daily doses (DDD) decreased from 7637 (last 3 months before change) to 6763 (including 610 PTAZ DDD) during the first 3-month period after change, due to a diminution of use of MERO and CEF use. [19]
The consumption of antibiotics was evaluated in Hospital de la Ribera, Valencia, Spain. Retrospective, cross-sectional study was made during three years (2000-2002). The authors studied and compared the annual consumption of anti-infectious, using as unit of measurement the DDD/100 stays for the hospitable consumption. In the Hospital, the antibiotics more consumed were: Amoxicillin-Clavulanic, Ciprofloxacin, Clarythromycin. Though out the period of study, a significant increase of the consumption also is detected to Cloxacillin (average increment/year = 0.2 points), Amoxicillin-Clavulanic (6.4 points), Cefotaxim (0.3 points), Imipenem (0.4 points), Gentamycin (0.6 points), Claythromycin and Vancomycin (0.4 points). [20].
Public hospitals are under financial pressure to contain pharmaceutical expenditure yet provide both established and innovative medicines for patients. In 2002, in an attempt to contain hospital drug expenditure, the New Zealand government agency PHARMAC began negotiating prices for some frequently used hospital medicines on behalf of all public hospitals. A recent study by Tordoff et al in the May/June 2005 issue of Value in Health examined the impact of the first year of this initiative. Using data provided by chief pharmacists from 11 hospitals (savings or costs for their Top150 items) the authors estimated projected savings of 3.7%, NZ$5.2m ($2.9m to $8.7m) for 2003/4 for all 29 major public hospitals. Two estimates for the 29 hospitals were obtained by extrapolating data from the 11 hospitals, using savings per bed, and savings per bed-day. Both estimates were similar. Smaller hospitals appeared to achieve better savings as a proportion of their expenditure. The main contributors to savings were agents for infections, the nervous system, musculoskeletal system, and blood/blood forming organs. The authors conclude that moderate cost
savings have been achieved but suggest effects on patient outcomes and the range of medicines available may need monitoring in future. [21]
2.6. Evaluation of LMWHs versus UFH
Low-molecular-weight heparins share many properties and are commonly referred to as a group, but structurally and pharmacologically they are dissimilar. The size spectrum of the heparin molecules varies between the different products and as assessed in vitro, their anticoagulant properties differ. In particular, the ratio anti-factor Xa : anti-factor IIa activities varies. The clinical consequences of these differences are unknown. The efficacy and safety of two different low-molecular-weight heparins have been compared in only a few clinical studies; no significant differences in outcome were shown. However, low-molecular-weight heparins should be used according to the approved indication for each product and in doses shown effective and safe in clinical studies. A change from one low-molecular-weight heparin to another in the same patient should be avoided. [22]
Low molecular weight heparins (LMWHs) differ from unfractionated heparin (UFH) in a number of characteristics, which is probably due to differences in molecular weight distribution. From a clinical point of view the better subcutaneous bioavailability and longer biological half-life are important, making it sufficient to inject LMWHs once-daily only. For practical purposes it is also important that LMWHs be used without monitoring. They are effective as prophylaxis against postoperative venous thromboembolism after all types of surgery; in most studies, more effective than UFH. In most studies, this effect can be obtained safely and with less bleeding than with UFH. LMWHs compare favourably with UFH for starting treatment of deep vein thrombosis, as well as an anticoagulant during haemodialysis. Adverse effects such as thrombocytopenia and osteoporosis are more common with UFH than with LMWHs. Studies evaluating whether or not LMWHs can replace UFH in arterial diseases are still few with small sample sizes. Thus further systematic research is needed. [23]
The low-molecular-weight heparins (LMWHs) have a number of therapeutic advantages, relative to standard unfractionated heparin (UFH). They are readily bioavailable when injected subcutaneously and can be given in fixed doses, allowing for far simpler administration. Several LMWHs are now commercially available, each demonstrating different physical and chemical
properties and different activities in animal models of anticoagulation or hemorrhage. In clinical comparisons with placebo in the treatment of unstable coronary artery disease (UCAD), the LMWHs dalteparin sodium and nadroparin calcium have demonstrated good anticoagulant efficacy. In comparisons with UFH, on the other hand, only enoxaparin has shown superior anticoagulant activity, as reported in the results of the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) and Thrombolysis In Myocardial Infarction (TIMI) 11B trials. However, close scrutiny of the methodology of the clinical trials in UCAD reveals considerable differences in study designs, dosage regimens, duration of administration of active treatments, and the timing and definition of endpoints. Therefore, it would not be scientifically sound to compare results with the different LMWHs based on the current available studies. It is also not possible to draw any conclusions with regard to the relative efficacy of the different LMWHs, since there are no properly-sized comparative data between dalteparin sodium, enoxaparin sodium, and nadroparin calcium. [24]
The results of the published trials have confirmed that the newer compounds are at least as safe and effective as unfractionated heparin offering considerable practical and clinical advantages. Low molecular weight heparins are currently recommended as alternative to unfractionated heparin in the acute management of acute coronary syndromes. Nevertheless, the different properties of these compounds and possibly the different designs of the clinical trials have resulted in apparent differences in clinical outcomes with the different agents. Direct comparisons are now required to determine the superiority of one compound over another. [25]
Consistent with the pooled data from trials of UFH, there wasa significant reduction in the rate of death or MI in aspirin-treatedpatients with unstable angina/non–ST-segment–elevationMI given dalteparin versus placebo (FRISC). Trials of LMWHs versusUFH in combination with aspirin are more difficult to interpret. Inanalyses that pool all LMWHs versus UFH, some authors have concludedthat there is no evidence of superiority of LMWH over UFH withrespect to prevention of death or MI. In addition to chemical differences in LMWHs and uncertainty about the relative antithromboticpotencies of the doses of the different LMWHs tested in thetrials. [26]
LMWHs and UFH in the treatment of: Thrombosis
Thromboembolic complications are a common and costly medical problem, associated with significant morbidity and mortality, especially in postoperative patients. There have been reports of death due to thromboembolic complications even after short procedures, e.g. arthroscopy. Low-molecular-weight heparins (LMWHs) (e.g., certoparin, dalteparin, enoxaparin, nadroparin, reviparin, tinzaparin) have been tested for treatment of deep vein thrombosis in comparison to unfractionated heparin (UFH) in many patients being effective and safe alternative for treatment of deep vein thrombosis (DVT) and venous thromboembolism (VTE). Fixed-dose subcutaneous LMWH once daily is in most cases of equivalent efficacy and safety compared to conventional UFH therapy. There may be less risk for bleeding, less platelet activation together with a control of markers of haemostatic system activation, and either no progression or regression of thrombus size in patients treated with LMWH. The handling of LMWH is more comfortable for patients and less time consuming for nurses and laboratories compared to UFH. Effectiveness and safety of LMWH (dalteparin, enoxaparin, nadroparin, tinzaparin) in comparison to UFH treatment on outpatient basis has been demonstrated in several studies. In summary, LMWHs have an established role in the treatment of DVT and pulmonary embolism (PE), on an in- and outpatient basis and could realize substantial savings. Most studies were performed with dalteparin, enoxaparin and nadroparin. There is evidence that LMWHs may help to prolong survival in cancer patients and to avoid complications of the acute coronary syndrome. [27]
Thromboembolism
Low molecular weight heparin (LMWH) has challenged the position of unfractionated heparin (UFH) as the treatment of choice in preventing progression, recurrence, and complications of venous thromboembolism (VTE). A meta-analysis of 13 randomized trials has shown that subcutaneous LMWH is associated with lower rates of recurrence, bleeding, and mortality than is intravenous UFH. The use of subcutaneous LMWH yields substantial savings in pharmacy and nursing costs. Recent trials have demonstrated that home treatment with enoxaparin and dalteparin is at least as safe and effective as inpatient treatment with UFH, is feasible in more than 70% of patients with VTE, and is associated with improved quality of life. [28]
Low-molecular-weight heparins (LMWHs) are rapidly becoming the anticoagulants of choice for the prevention and treatment of venous thromboembolism. LMWHs are at least as safe and effective as unfractionated heparin, and they have the added advantage of improved pharmacokinetic and safety profiles. The result is that LMWHs are easier to use, provide a more predictable anticoagulant effect, and do not require routine laboratory monitoring in most circumstances. [29]
OBJECTIVES: To compare the efficacy and safety of unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) and to examine current controversies in the treatment of venous thromboembolism (VTE) (ie, setting, product type, and frequency of administration). METHODS: Data were abstracted from MEDLINE, HEALTH, previous reviews, personal files, clinical experts, and conference abstracts. Randomized controlled trials of patients diagnosed with acute VTE that compared LMWHs with UFH were included. Independent duplicate assessment was done for methodological quality and data extraction. Data are reported as pooled relative risks (RRs) and 95% confidence intervals (CIs) comparing LMWHs with UFH as determined by the random effects model. RESULTS: Thirteen studies were included. There was no statistically significant difference in risk between UFH and LMWHs for recurrent VTE (RR, 0.85 [95% CI, 0.65-1.12]), pulmonary embolism (RR, 1.02 [95% CI, 0.64-1.62]), major bleeding (RR, 0.63 [95% CI, 0.37-1.05]), minor bleeding (RR, 1.18 [95% CI, 0.87-1.61]), and thrombocytopenia (RR, 0.85 [95% CI, 0.45-1.62]). There was a statistically significant difference for risk of total mortality (RR, 0.76 [95% CI, 0.59-0.98]) in favor of LMWHs. Inpatient treatment may reduce the risk of major bleeding vs outpatient therapy. Once-daily therapy is as safe and effective as twice-daily therapy when compared indirectly. Different products could not be statistically compared, but qualitative analysis shows that there are no apparent differences in efficacy and safety. CONCLUSIONS: Low-molecular-weight heparins are at least as effective as UFH in preventing recurrent VTE. It is unlikely that LMWHs are superior in the treatment of VTE, but they do show a statistically significant decrease in total mortality. No differences were seen in the development of recurrent VTE dependent on treatment setting. There were no apparent differences between once-daily and twice-daily therapy or among products. Inpatient therapy may be associated with less major bleeding; therefore, if LMWHs are given in the outpatient setting, patients should be rigorously monitored. [30]
Acute Coronary Syndromes
Platelet aggregation, and activation of coagulation cascade are the key events in the development of acute coronary syndromes (ACS). Patients with this syndrome are at high risk of adverse events, such as death and myocardial infarction (MI). Optimized medical treatment for the non-ST segment elevation ACSs should consist of a combined thrombotic/anginal regimen. Standard anti-thrombotic treatment is currently unfractionated heparin (UH) and aspirin, and in high-risk patients glycoprotein IIb/IIIa inhibitors. UH has been shown to reduce the risk of death or myocardial infarction in aspirin-treated patients with ACSs, but it has a number of limitations, such as need for regular monitoring and the risk of hemorrhage and thrombocytopenia. Compared to UH, the low molecular weight heparins (LMWH) possess several important theoretical advantages for the treatment of patients with ACSs, including less non-specific binding, resistance to inactivation by platelet factor-4, more reliable anticoagulation effects, and greater factor anti-Xa activity. Recently published trials strongly support the use of LMWHs in the treatment of ACSs. These agents provide an alternative to UH that is at least as effective. The available evidence favours the use of these agents in acute cardiac care. [31]
CONTEXT: Low-molecular-weight heparins (LMWHs) possess several potential pharmacological advantages over unfractionated heparin as an antithrombotic agent. OBJECTIVE: To systematically summarize the clinical data on the efficacy and safety of LMWHs compared with unfractionated heparin across the spectrum of acute coronary syndromes (ACSs), and as an adjunct to percutaneous coronary intervention (PCI). DATA SOURCES: The authors searched MEDLINE for articles from 1990 to 2002 using the index terms heparin, enoxaparin, dalteparin, nadroparin, tinzaparin, low molecular weight heparin, myocardial infarction, unstable angina, coronary angiography, coronary angioplasty, thrombolytic therapy, reperfusion, and drug therapy, combination. Additional data sources included bibliographies of articles identified on MEDLINE, inquiry of experts and pharmaceutical companies, and data presented at recent national and international cardiology conferences. STUDY SELECTION: They selected for review randomized trials comparing LMWHs against either unfractionated heparin or placebo for treatment of ACS, as well as trials and registries examining clinical outcomes, pharmacokinetics, and/or phamacodynamics of LMWHs in the setting of PCI. Of 39 studies identified, 31 fulfilled criteria for analysis. DATA EXTRACTION: Data quality was determined by publication in the peer-reviewed
literature or presentation at an official cardiology society-sponsored meeting. DATA SYNTHESIS: The LMWHs are recommended by the American Heart Association and the American College of Cardiology for treatment of unstable angina/non-ST-elevation myocardial infarction. Clinical trials have demonstrated similar safety with LMWHs compared with unfractionated heparin in the setting of PCI and in conjunction with glycoprotein IIb/IIIa inhibitors. Finally, LMWHs show promise as an antithrombotic agent for the treatment of ST-elevation myocardial infarction. CONCLUSIONS: The LMWHs could potentially replace unfractionated heparin as the antithrombotic agent of choice across the spectrum of ACSs. In addition, they show promise as a safe and efficacious antithrombotic agent for PCI. However, further study is warranted to define the benefit of LMWHs in certain high-risk subgroups before their use can be universally recommended. [32]
3.
OBJECTIVE
To evaluate the consumption of medicines in Hospital of Kaunas University of Medicine (HKUM) in the year 2001-2005.
4. AIMS
1. To analyze the utilization of medicines in Hospital of Kaunas University of Medicine during the five-year period from the financial standpoint; also to compare the mostly consumed medicines in units.
2. To evaluate the utilization of medicines in Hospital of Kaunas University of Medicine by the means of the DDD methodology.
3. To perform Meta-Analysis for Heparins (low-molecular-weight heparins versus unfractionated heparin); also to adopt pharmacoeconomical analysis using cost minimisation and reference price methodologies.
4. To evaluate tendencies of Antibiotics utilization from the financial stand-point and by the means of the DDD methodology.
5. METHODOLOGY
5.1. The purpose of the ATC/DDD system
The purpose of the ATC/DDD system is to serve as a tool for drug utilization research in order to improve quality of drug use. One component of this is the presentation and comparison of drug consumption statistics at international and other levels. A major aim of the Centre and Working Group is to maintain stable ATC codes and DDDs over time to allow trends in drug consumption to be studied without the complication of frequent changes to the system. There is a strong reluctance to make changes to classifications or DDDs where such changes are requested for reasons not directly related to drug consumption studies. For this reason the ATC/DDD system by itself is not suitable for guiding decisions about reimbursement, pricing and therapeutic substitution. [34]
5.2. The ATC classification – structure and principles
Structure
In the Anatomical Therapeutic Chemical (ATC) classification system, the drugs are divided into different groups according to the organ or system on which they act and their chemical, pharmacological and therapeutic properties. Drugs are classified in groups at five different levels. The drugs are divided into fourteen main groups (1st level), with one pharmacological/therapeutic subgroup (2nd level). The 3rd and 4th levels are chemical/pharmacological/therapeutic subgroups and the 5th level is the chemical substance. The 2nd, 3rd and 4th levels are often used to identify pharmacological subgroups when that is considered more appropriate than therapeutic or chemical subgroups.
Principles for classification
Medicinal products are classified according to the main therapeutic use of the main active ingredient, on the basic principle of only one ATC code for each pharmaceutical formulation (i.e. similar ingredients, strength and pharmaceutical form). A medicinal product can be given more than one ATC code if it is available in two or more strengths or formulations with clearly different therapeutic uses. A medicinal product may be used for two or more equally important indications,
several classification alternatives. Such drugs are usually only given one code, the main indication being decided on the basis of the available literature. Problems are discussed in the WHO International Working Group for Drug Statistics Methodology where the final classification is decided. Cross-references will be given in the guidelines to indicate the various uses of such drugs. The ATC system is not strictly a therapeutic classification system. At all ATC levels, ATC codes can be assigned according to the pharmacology of the product. Subdivision on the mechanism of action will, however, often be rather broad, since a too detailed classification according to mode of action often will result in having one substance per subgroup which as far as possible is avoided. Some ATC groups are subdivided in both chemical and pharmacological groups. If a new substance fits in both a chemical and pharmacological 4th level, the pharmacological group should normally be chosen. Substances classified in the same ATC 4th level cannot be considered pharmacotherapeutically equivalent since their mode of action, therapeutic effect, drug interactions and adverse drug reaction profile may differ.
5.3. The DDD – definition and principles
The basic definition of the unit is:
The DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults. A DDD will only be assigned for drugs that already have an ATC code.
It should be emphasized that the defined daily dose is a unit of measurement and does not necessarily reflect the recommended or prescribed daily dose. Doses for individual patients and patient groups will often differ from the DDD and will necessarily have to be based on individual characteristics (e.g. age and weight) and pharmacokinetic considerations. Drug consumption data presented in DDDs only give a rough estimate of consumption and not an exact picture of actual use. DDDs provide a fixed unit of measurement independent of price and formulation enabling the researcher to assess trends in drug consumption and to perform comparisons between population groups.
DDDs are not established for topical preparations, sera, vaccines, antineoplastic agents, allergen extracts, general and local anesthetics and contrast media.[35]
5.4. Drug utilization
The ATC/DDD system can be used for collection of drug utilization statistics in a variety of settings and from a variety of sources.
Examples are:
• Sales data such as wholesale data at a national, regional or local level.
• Dispensing data either comprehensive or sampled. In many countries pharmacies are computerized and advantage can be taken of this to collect data on drugs dispensed. Alternatively, sample data can be collected manually. Reimbursement systems, which operate in a number of countries at the national level, provide comprehensive dispensing data down to the individual prescription level, as all prescriptions are submitted and recorded for reimbursement. This is generally called "claims" data. Similar data are often available through health insurance or health maintenance organizations. These databases can sometimes allow collection of demographic information on the patients, and information on dose, duration of treatment and co-prescribing. Less commonly, linkage to hospital and medical databases can provide information on indications, and outcomes such as hospitalization, use of specific medical services and adverse drug reactions.
• Patient encounter based data. This is usually collected by specially designed sampling studies such as those carried out by market research organizations. However, increasing use of information technology at the medical practice level will make such data available more widely in the near future. These methods have the advantage of potentially providing accurate information on Prescribed Daily Doses, patient demographics, duration of therapy, co-prescribing, indications, morbidity and co-morbidity, and sometimes outcomes.
• Patient survey data. Collection of data at the patient level can provide information about actual drug consumption and takes into account compliance in filling prescriptions and taking medications as prescribed. It can also provide qualitative information about perceptions, beliefs and attitudes to the use of medicines.
• Health Facility data. Data on medication use at all the above levels is often available in health care settings such as hospitals and health centers at regional, district or village level. [36]
5.5. Definition of Cost-minimization analysis
Cost-minimization analysis compares the costs of two or more treatment alternatives that have a demonstrated equivalence in therapeutic outcome. This type of analysis is used when searching for the lowest cost alternative between competing therapies for formulary inclusion. [37]
The cost-minimization compares the costs of two or more therapies that have equivalent treatment outcomes. To declare therapies equivalent, a proper equivalency trial is necessary. The objective of an equivalency trial is to demonstrate that drug A is at least as good as drug B.
Before undertaking this type of trial, a minimally clinically important difference (MCID) in the treatment outcome must be estimated. The MCID is defined as the smallest improvement in the outcome measure that is perceived as beneficial. In the case of mortality, there is no consensus as to what constitutes a MCID, but it is generally accepted that if the treatment benefit from two competing therapies does not differ by more than 1% in total mortality, the therapies can be considered to be-equivalent. To determine the MCID for treatment outcomes other than mortality, a formal literature search and/or a consensus conference is required. Using this a priori estimate of a MCID, the number of patients required to demonstrate equivalency can then be calculated.
Sample size calculations for equivalency trials are performed using a statistical power of 90% or greater. In this way, when the trial reports no statistically significant difference between the two therapies, the reader can be at least 90% sure that a difference greater than the MCID does not exist. Equivalency trials and thus cost-minimization studies, are very difficult to conduct and as a basic rule, if a MCID is not defined in advance or if a sample size calculation is not performed using at least 90% power, the two therapies cannot be declared equivalent. Since equivalency trials can be complex to design, conduct and report, the excellent paper by Massel provides a detailed approach to a critical review of the topic.
If an appropriate sample size calculation is performed using at least 90% power and if a MCID is defined in advance, the cost minimization study resolves to a simple, direct comparison of the difference between the total costs recorded in both arms of the trial. [38]
5.6. Reference pricing
The immediate intuitive appeal of reference pricing is clear – to pay a similar price for products that provide a similar benefit. From the payer’s perspective, it provides an opportunity to reduce the cost of higher-priced products – to pay only the lowest common denominator, the generic price.
Reference pricing for medicines must be viewed within the context of the cost-containment pressures being faced by healthcare systems everywhere. Although it is a relatively small component of the overall healthcare budget, expenditure on medicines is the fastest-growing component. Analysis of the factors contributing to the growth in pharmaceutical expenditure in major markets shows that the biggest factor is innovation, as physicians switch from older to newer and more effective medicines.
However, reference pricing has negative consequences for both patients and pharmaceutical innovation. What it fails to take into account is the variety of both products and patients. Products within the same class may have characteristics that differ in clinically significant ways, and much innovation comes from incremental improvement within therapeutic classes. But, if new products will be clustered with existing products there is no incentive for companies to invest in such incremental improvement. The almost infinite variability of patients may mean that, for an individual patient, only one medicine in a class may be effective or appropriate.
No two reference pricing schemes are identical, but the essential elements are:
• The grouping together of medicines into identical or similar classes (often known as clusters), whether by active substance or therapeutic class. In most countries this clustering is restricted to generic medicines, but in Germany and the Netherlands patent-protected medicines may be included. The assumption is that products in a cluster are interchangeable.
• A fixed maximum reimbursement price is set for all the medicines within the cluster, irrespective of their actual prices. Usually this is set by reference to the cheapest medicines within the cluster.
• Manufacturers are free to set the price of their products above the reference price (the reimbursed amount), but patients are responsible for paying co-payments where the price exceeds the reference price. [39]
5.7. Meta-analysis methodology
Meta-analysis is a statistical procedure that integrates the results of several independent studies considered to be "combinable." Well conducted meta-analyses allow a more objective appraisal ofthe evidence than traditional narrative reviews, provide a more precise estimate of a treatment effect, and may explain heterogeneitybetween the results of individual studies. [40]
Meta-analysis should be viewed as an observational study of the evidence. The steps involved are similar to any other researchundertaking: formulation of the problem to be addressed, collectionand analysis of the data, and reporting of the results.
As with criteria for including and excluding patients in clinicalstudies, eligibility criteria have to be defined for the data to be included. Criteria relate to the quality of trials and to the combinability of treatments, patients, outcomes, and lengths of follow up. Quality and design features of a studycan influence the results.
The strategy for identifying the relevant studies should beclearly delineated. In particular, it has to be decided whetherthe search will be extended to include unpublished studies,as their results may systematically differ from published trials.As will be discussed in later articles, a meta-analysis thatis restricted to published evidence may produce distorted resultsowing to such publication bias. For locating published studies,electronic databases are useful.
Individual results have to be expressed in a standardized formatto allow for comparison between studies. If the end point is continuous, the mean difference between the treatment and control groups is used. The size ofa difference, however, is influenced by the underlying population value. Differencesare therefore often presented in units of standard deviation. Ifthe end point is binary—for example, disease versus nodisease, or dead versus alive) then odds ratios or relative risks are often calculated. The odds ratio has convenientmathematical properties, which allow for ease in combining dataand testing the overall effect for significance. Absolute measures,such as the absolute risk reduction or the number of patientsneeded to be treated to prevent one event, are more helpfulwhen applying results in clinical practice.
The last step consists in calculating the overall effect by combining the data. A simple arithmetic average of the resultsfrom all the trials would give misleading results. The results from small studies are more subject to the play of chance and should therefore be given less weight. Methods used for meta-analysis use a weightedaverage of the results, in which the larger trials have
moreinfluence than the smaller ones. The statistical techniquesto do this can be broadly classified into two models, thedifference consisting in the way the variability of the resultsbetween the studies is treated. The "fixed effects" model considers,often unreasonably, that this variability is exclusively dueto random variation. Therefore, if all the studies were infinitely large theywould give identical results. The "random effects" modelassumesa different underlying effect for each study and takes this into consideration as an additional source of variation, which leads to somewhat wider confidence intervals than the fixed effectsmodel. Effects are assumed to be randomly distributed, and the central point of this distribution is the focus of the combined effect estimate. Although neither of two models can be said to be "correct,"a substantial difference in the combined effect calculated by the fixed and random effects models will be seen only if studies are markedly heterogeneous. [41]
If the results of the studies differ greatly then it may notbe appropriate to combine the results. How to ascertain whetherit is appropriate, however, is unclear. One approach is to examine statistically the degree of similarity in the studies' outcomes—in other words, to test for heterogeneity across studies. In such procedures, whether the results of a study reflect a single underlying effect,rather than a distribution of effects, is assessed. If this test shows homogeneous results then the differences betweenstudies are assumed to be a consequence of sampling variation, anda fixed effects model is appropriate. If, however, the testshows that significant heterogeneity exists between study results then a random effects model is advocated. Although there is no statistical solution to this issue, heterogeneitybetween study results should not be seen as purely a problem for meta-analysis—it also provides an opportunity for examining why treatment effects differ in different circumstances. Heterogeneityshould not simply be ignored after a statistical test is applied;rather, it should be scrutinized, with an attempt to explainit. [42]
6. RESULTS
6.1. Financial analysis of drug utilization.
The total drug expenses in the five-year period increased significantly from 5.261 thousand Lt in 2001 to 9.804 thousand Lt in 2005.
More detailed results can be seen in Figure 1.
Total Drug Expenses
- Lt 2.000.000,00 Lt 4.000.000,00 Lt 6.000.000,00 Lt 8.000.000,00 Lt 10.000.000,00 Lt 12.000.000,00 Lt 2001 2002 2003 2004 2005
Fig.1. Total drug expenses from 2001 to 2005 in HKUM.
In addition to that, the most popular medicines were also taken into consideration, they there divided into three groups, the first one of 10 most expensive drugs (TOP10), the second one – 20 most expensive medicines (TOP20) and the third one of 30 most expensive drugs (TOP30). Every year expenses for these groups of drugs can be seen in Figure 2. There the total costs of TOP groups are compared with the general drug expenses in the year 2001-2005. During those years the expenses were increasing in all groups.
Total Drug Expenses in Comparison with TOP30, TOP20, TOP10 (t. Lt) 0 2000 4000 6000 8000 10000 12000 2001 2002 2003 2004 2005 Total Expenses TOP30 TOP20 TOP10
Fig 2. Comparison of total drug expenses with TOP30, TOP20, TOP10.
From 2001 to 2005 the expenses for the medicines in HKUM totally increased by 46,34%, reaching the average rise of 17,14% a year. The similar tendencies can be noticed in the groups of the most expensive drugs – TOP30, TOP20 and TOP10. As one can see from Figure 3, the most important was the last period (2004-2005), when the growth of general expenses was 32%. In the previous years the growth was smaller than the average, with the dip in 2002-2003, when the growth did not reach 10% barrier.
It is important to state that the growth of expenses in the TOP groups was higher than the overall one. From 2001 to 2005 the costs of TOP30 increased by 48%, of TOP20 – 49 % and of TOP10 – 52%. This means significantly larger amount of money was allocated only to 10 most expensive medicines. The yearly average growth in those TOP groups was following: TOP30 – the average of 18,43%, TOP20 – 19,42%, and TOP10 – 37.84%. Apparently, the growth of the costs of TOP10 medicines is twice as high as the growth of the other total costs.
As we can see the trends of TOP medicines in Figure 3 have one similar feature – they all suddenly decreased in the year 2002-2003. Then the average growth of the costs of TOP30, TOP20 and TOP10 drugs did not reach 5% barrier, but in the same period the growth of total costs was almost 10%.
In the first period the growth of costs of the TOP groups was two to three times greater than the growth of total costs, during the next two periods the situation completely changed, and the total costs showed slightly higher increase. In the last year the TOP groups overcame the growth of total costs by 5-10%, Growth of Expenses 0,00% 5,00% 10,00% 15,00% 20,00% 25,00% 30,00% 35,00% 40,00% 45,00% 2001-2002 2002-2003 2003-2004 2004-2005
Total Expenses Growth TOP30 Expenses Growth TOP20 Expenses Growth TOP10 Expenses Growth
Fig. 3. Growth of expenses.
Also the expenses for TOP30, TOP20 and TOP10 most expensive drugs were evaluated. The results show that approximately one third of the whole money spent on medicines was allocated only to 10 drugs, 45-48% of money went to TOP20 and almost 60% to TOP30. Those tendencies remain almost the same trough out the whole five-year period, with the slight peek in 2002. Figure 4.
Dynamics of TOP30, TOP20, TOP10 Drug Expenses 0,00% 10,00% 20,00% 30,00% 40,00% 50,00% 60,00% 70,00% 2001 2002 2003 2004 2005
TOP30 Drug Expenses TOP20 Drug Expenses TOP10 Drug Expenses
Fig. 4. Dynamics of drug expenses.
As the overall drug expenses were increasing from 2001 to 2005, the same trend could be noticed in the TOP groups. As it is seen from the Figure 5 below, the expenses for TOP30 medicines increased almost twice, from 3.000 thousand Lt in 2001 to almost 6.000 thousand Lt in 2005. The groups of TOP20 and TOP10 had the same double increase in the mentioned period of time.
From 2001 to 2002 the increase of the expenses of the TOP30, TOP20 and TOP10 medicines was fairly noticeable, but not very significant, approximately 500-800 thousand Lt in every group. Though from 2002 to 2004 the trend remained the same, only with slight increase from the year 2003. The most crucial was the period from 2004 to 2005, then the expenses for the TOP medicines increased almost 1.3 times, which was, saying in currency, more than a million Lt for each group. This is very important, because despite the fact that in the same year overall drug expenses were also 1.3 time greater, the extra money was again allocated to the same TOP groups, so to the most expensive drugs.
Expenses increase of TOP30, TOP20, TOP10 (t. Lt) 0 1000 2000 3000 4000 5000 6000 2001 2002 2003 2004 2005 TOP30 TOP20 TOP10
Fig. 5. Expenses increase of TOP30, TOP20, TOP10.
6.2. Analysis of drug utilization in units.
The consumption of medicines in HKUM in 2001-2005 was analysed also in units. There a unit can be defined as one sample of the drug form: tablet, capsule, ampoule, etc. 10 most popular drugs of that period were taken into consideration. It can be determined from the Figure 6 below that the variation of medicines in those TOP10 groups was limited. The same medicines remained in the leading position though out the years.
The most stable trends were shown by two medicines – Penicillin and Diazepam. The first one remained in the TOP 5 during the whole period, with approximately 150-200 thousand units per year, and Phentanylum that managed to stay in TOP 10 with almost 100 thousand units.
The rest of drugs used to change their position, sometimes disappearing from the list or reappearing later on.
The leaders of the list are three medicines. In the first two years the significant leader was Diazepam with a peak in 2002, then 350 thousand units of it were consumed. Though in 2003 there was a huge drop and since then the trend remained stable with the average value of 200 thousand units. The most popular medicine in 2005 was Ranitidinum, almost 250 thousand units of it were
utilized. Ranitidinum used to be a TOP 3 drug during the five-year-period with a rather obvious increase in 2004. Ketorolacum was very popular from 2001 to 2004, the peak of usage was in 2003 – almost 300 thousand units, but in 2005 there was a dramatic decrease, that year only 150 thousand units were consumed.
Other drugs did not manage to stay in TOP 10 group through out the years. Analginum appeared only in 2002 with 200 thousand units at once, the trend remained stable until 2004, later a big decrease followed. Lidocainum has been TOP 10 medicine since 2004, but in 2005 the results were quiet poor - a dropped by almost 50 thousand units.
The rest three examples – Diclofenacum, Daxamethasonum and Prednisolonum disappeared in 2004 and did not return to TOP 10 even in 2005.
Changes in TOP10 Group in Units
0 50000 100000 150000 200000 250000 300000 350000 400000 2001 2002 2003 2004 2005 Ranitidinum (tab.) Diazepamum Penicillinum Ketorolacum Phentanylum Analginum Diclofenacum Dexamethasonum Prednisolonum Lidocainum
Fig. 6. Changes in TOP10 group in units.
6.3. Analysis of drug consumption in DDD.
The tendency of medicines consumption in the value of DDDs per 1000 hospitalization days was rather similar to the one in units. See Figure 7 below. The usage was analyzed using the value of the defined dosage (DDD) per 1000 hospitalization-days (DDD/1000 HD).
First of all the latest tendency, i.e. the results of the mostly consumed medicines in the year 2005 were taken into consideration, the values of the previous years were added.
Ketorolacum and Dexamethasonum seemed to be the most highly consumed drugs in the five year period. The trend of Ketorolacum performed some changed during the mentioned period, the peak of value was in 2003 – 311.53 DDDs per 1000 hospitalization days. The second really popular medicine is Dezamethasonum, it also managed to keep the value above the value of 200 DDDs per 1000 hospitalization days from 2001 to 2005, the peak was in 2004 with the meaning of 296.69.
The following examples were Ranitidinum and Diazepamum. Both medicines managed to keep the trend rather stable between the values of 150 and 200 DDDs per 1000 hospitalization days.
In addition, Prednisolonum showed the opposite tendency, from 2001 to 2002 the mentioned value did not reach the barrier of 100 DDD/1000 HD, but in the year 2003 it increased dramatically, i.e. more than twice, reaching the value of 205.84 DDDs per 1000 hospitalization days. Despite that, afterwards a significant decrease followed, and in 2005 the value was only 87.66.
The next three medicines – Penicillinum, Analginum, Enalaprilum demonstrated a stable trend, the meaning of DDD/1000 HD varied slightly above or below 100. The trend of Diclofenacum was rather similar, the only difference is the peak in 2004 representing the meaning of 152.95 DDDs per 1000 hospitalization days.
The last drug on the list was Omeprazolum, in 2005 it had the meaning of 75.51 DDDs per 1000 hospitalization days, though in the previous years the value was not significant, and varied from 15 to 30 DDD/1000 HD. The situation changed in the year 2004, when it reached the value of 67.74 DDDs per 1000 hospitalization days.
DDD/1000 HD Changes of Mostly Consumed Drugs 0 50 100 150 200 250 300 350 2001 2002 2003 2004 2005 Ranitidinum (tab.) Diazepamum Penicillinum Ketorolacum Prednisolonum Analginum Diclofenacum Dexamethasonum Omeprasolum Enalaprilum (tab.)
Fig. 7. DDD/1000 HD changes of mostly consumed drugs.
6.4.1 Analysis of Heparins consumption.
One of the most frequently used medicines are Heparins – Low molecular weight heparins (LMWH) and unfractionized heparins (Heparin). They take approximately 6-8% of the total drug expenses yearly. Figure 8. The part of money spent on this group of medicines remained stable, only minor changes could be noticed.
Share of Heparins cost 0,00% 1,00% 2,00% 3,00% 4,00% 5,00% 6,00% 7,00% 8,00% 9,00% 2001 2002 2003 2004 2005
Fig. 8. Share of heparins costs.
Still, as the drug expenses were increasing dramatically, so did the group of Heparins. Total cost of heparins is shown in Figure 9. There one can see that from 2001 the total Heparins cost increased twice and reached the sum of 700 thousand Lt in 2005, whereas in 2001 it was only 350 thousand Lt. The year 2003 and 2005 had the greatest impact on that, the increase was almost 50% both times. During the other periods the growth was not significant. See Figure 9.
Cost of Heparins - Lt 100.000,00 Lt 200.000,00 Lt 300.000,00 Lt 400.000,00 Lt 500.000,00 Lt 600.000,00 Lt 700.000,00 Lt 800.000,00 Lt 2001 2002 2003 2004 2005
In HKUM from 2001 the following Heparins were being used: Nandroparinum (Fraxiparine), Enoxaparinum (Clexane), Heparinum, Tinzaparinum (Innohep) that actually disappeared in 2005 and Dalteparinum natricum (Fragmin) that only appeared in 2005 at once reaching the value of 74.11 DDDs per 1000 hospitalization days, and the total cost of 189 thousand Lt. The variations of total costs, single DDD price and DDD per 1000 hospitalization days of the first three medicines were taken into consideration.
First of all the results of Nadroparinum were evaluated. The total costs of this LMWH can be seen in Figure 10. There one can notice that the costs of Fraxiparine were increasing from 2001 to 2004, then the peak was reached and more than 400 thousand Lt were spent on it. Though in 2005 the drop of almost 150 thousand Lt appeared.
Cost (Lt) 0,00 50000,00 100000,00 150000,00 200000,00 250000,00 300000,00 350000,00 400000,00 450000,00 2001 2002 2003 2004 2005 Cost (Lt)
Fig. 10. Cost of Nadroparinum.
Next important value that was also estimated – the number of DDDs per 1000 hospitalization days. The trend of this parameter can be seen in Figure 11. The overall tendency of this chart is very similar to the trend of total costs. Still here the value of DDDs per 1000 hospitalization days increased from 41.56 in 2001 to 134.31 in 2004. In the year 2005 there was a significant drop in this value, the result was 78.90.
Number of DDDs per 1000 hospitalization days 0 20 40 60 80 100 120 140 160 2001 2002 2003 2004 2005
Fig. 11. Number of DDDs per 1000 HD.
The trend of single DDD price was rather different. The price of single DDD of Fraxiparine was decreasing from 2001 to 2004. Though in 2005 it suddenly increased up to 6.05 Lt per DDD. See Figure 12 below.
Single DDD Price (Lt) 0 1 2 3 4 5 6 7 8 9 10 2001 2002 2003 2004 2005 1 DDD Price (Lt)
Fig.12. Single DDD price of Nadroparinum.
The next example is Heparin. The costs of this medicine did not vary a lot during the whole five-year period. See Figure 13. Only a slight dip was be noticed in 2002, when the expenses for Heparin did not reach 70 thousand Lt per year.
Cost (Lt) 0,00 20000,00 40000,00 60000,00 80000,00 100000,00 120000,00 2001 2002 2003 2004 2005 Cost (Lt)
Fig.13. Cost of UFH.
However the value of DDD per 1000 hospitalization days shifted heavily from 2001 to 2005. See Figure 14. The highest meaning was in 2003 – 91.37 DDDs per 1000 hospitalization days, but in 2004 it decreased more than three times up to the 27.01, one year later it recovered and reached the value of 63.40 DDDs per 1000 hospitalization days.
Number of DDDs per 1000 hospitalization days
0 10 20 30 40 50 60 70 80 90 100 2001 2002 2003 2004 2005
Fig.14. Number of DDDs per 1000 HD for UFH.
One more evaluated parameter was single DDD Price. The trend of its variation can be seen in Figure 15. Single DDD price of Heparin used to be approximately 2.00 Lt, the only exception was in the year 2004, when it increased 3.2 times, from 1.49 Lt in 2003 up to 4.80 Lt in 2004.
Single DDD Price (Lt) 0 1 2 3 4 5 6 2001 2002 2003 2004 2005 1 DDD Price (Lt)
Fig.15. Single DDD price of UFH.
The last example in the list mentioned earlier was Enoxaparinum (Clexane). The same three values were also estimated for this drug. In the beginning the total costs of this heparin were taken into consideration. The results can be seen below, Figure 16. The costs used to be rather small until 2005 when they increased dramatically that means almost 5 times, from 27 thousand Lt in 2004 up to 135 thousand Lt in 2005. Cost (Lt) 0,00 20000,00 40000,00 60000,00 80000,00 100000,00 120000,00 140000,00 160000,00 2001 2002 2003 2004 2005 Cost (Lt)
Figure 17 shows the trend of the value of DDDs per 1000 hospitalization days. The changes of this parameter simply repeated the trend of costs. From 2001 to 2004 the value even did not hit the number of 10 DDDs per hospitalization days, but in the year 2005 the situation suddenly changed. Then the mentioned parameter increased about 5 times, from 6.35 to 29.55.
Number of DDDs per 1000 hospitalization days
0 5 10 15 20 25 30 35 2001 2002 2003 2004 2005 DDD per 1000 hospitalization days
Fig.17. Number of DDDs per 1000 HD of Enoxaparinum.
The last evaluated parameter was single DDD Price. The trend of its variation can be seen in Figure 18. Single DDD price of Enoxaparin used to be vary from 9.21 Lt in 2001 to 7.62 Lt in 2005, the dip of this value was in the year 2004 – 7.30 Lt. See Graph 21.
Single DDD Price (Lt) 0 1 2 3 4 5 6 7 8 9 10 2001 2002 2003 2004 2005
6.4.2 Meta-Analysis of Heparins
A meta-analysis of randomized studies which directly compared the effectiveness of low molecular weight heparins (LMWH) i.e. Nadroparinum (Fraxiparine), Enoxaparinum (Clexane), Tinzaparinum (Innohep) and Dalteparinum (Fragnim) with unfractionated heparin (UFH) was performed. A literature search was performed using Advanced Pub Med database and abstracts from recent meetings were reviewed. The articles that were taken into consideration can be seen in tables 8 – 13 (see ANNEX 6 -11 below).
The specified efficacy end point of interest included a composite of death, myocardial infarction, recurrent angina, deep vein thromboembolism, pulmonary embolism and urgent revascularization. The safety end points was taken as a composite of major hemorrhage, minor hemorrhage, thrombocytopenia, allergic reaction and any other adverse event. These safety end points were not included in the calculations.
The statistical software MedCalc was used to perform the estimations of different values. We calculated the values of effect size and odds ratio (95% confidence interval) for each trial for the composite end point.
The results were as following:
Table 1. Date from the performed heparins Meta-analysis.
Compared medicines Number of studies Effect size Odds ratio 95% CI P
1 UFH vs. Dalteparinum 12 1,0250 1,024 0,750 - 1,397 0,0165 2 UFH vs. Nadroparinum 9 0,9686 0,481 0,285 - 0,812 <0,0001 3 UFH vs. Enoxaparinum 17 0,9428 0,696 0,591 - 0,821 <0,001 4 UFH vs. Tinzaparinum 4 0,9303 0,384 0,190 - 0,776 0,2825 6 Enoxaparinum - Dalteparinum 3 1,1019 1,379 0,807 - 2,355 0,7842 7 Enoxaparinum - Tinzaparinum 2 1,1020 1,463 0,597 - 3,590 0,0149
The main aim of the performed Meta-analysis was to compare unfrationated heparin with every of four low-molecular-weight heparins (Dalteparinum, Nadroparinum, Enoxaparinum, Tinzaparinum) from the efficacy stand – point. Later on, it was also important to compare all LMWHs with each other.
UFH vs. Dalteparinum:
Twelve studies, involving 3993 patients, were eligible. There were no statistically significant differences in the efficacy values of those two medicines (odds ratio 1.024, 95% confidence interval 0.750 – 1.397).
UFH vs. Nadroparinum:
Nine studies, involving 8283 patients in total, were eligible. There was a statistically significant difference in the efficacy values of those two medicines (odds ratio 0.481, 95% confidence interval 0.285 – 0.812). Meta-analysis 0,0001 0,1 100 Odds ratio 1 2 3 4 5 6 7 8 9
Total (fixed effects) Total (random effects)
Meta-analysis 0,01 1 100 Odds ratio 1 2 3 4 5 6 7 8 9 10 11 12
Total (fixed effects) Total (random effects)
UFH vs. Enoxaparinum:
Seventeen studies, involving 34801 patients in total, were eligible. There was a statistically significant difference in the efficacy values that were estimated (odds ratio 0.696, 95% confidence interval 0.591 – 0.821).
UFH vs. Tinzaparinum:
Four studies, involving 884 patients, were eligible. There was rather a significant difference in the efficacy values that were estimated (odds ratio 0.384, 95% confidence interval 0.190 – 0.776).
Meta-analysis 0,01 0,1 1 10 Odds ratio 1 2 3 4
Total (fixed effects) Total (random effects)
