KAUNAS UNIVERSITY OF MEDICINE FACULTY OF PHARMACY
DEPARTMENT OF BASIC AND CLINICAL PHARMACOLOGY
TRENDS IN THE USE OF STATINS IN LITHUANIA ON 2005 – 2007 YEARS
MASTER WORK
Supervised by:
Edmundas Kaduševičius, MD., PharmD., PhD., Assoc. professor of clinical pharmacology Performed by:
Inga Paulauskait÷, Faculty of Pharmacy 5/5 gr
TABLE OF CONTENTS
ABBREVIATIONS………...4
1. INTRODUCTION……….5
2. STATINS FOR THE PREVENTION AND TREATMENT OF CARDIOVASCULAR DISEASE 2.1 About cholesterol……….7
2.2 CVD: etiology, pathology and prognosis………...8
2.3 Cholesterol-lowering therapy: getting statins………11
2.3.1 Dosage……….12
2.3.2 Effectiveness………...13
2.3.3 Labelled indications for statins use……….14
2.3.4 How do statins work? ...16
2.3.5 Non-lipid effects of statins………..17
2.3.6 Pharmacokinetics of HMG-CoA reductase inhibitors………19
2.3.7 Metabolism……….21
2.3.8 Safety issues with statin therapy……….22
2.3.9 Recommendations for treatment……….26
3. OBJECTIVE AND AIMS………31
4. MATERIAL AND METHODS………...32
4.1 The purpose of the ATC/DDD system………...32
4.2 The ATC classification – structure and principles……… 32
4.3 The DDD – definition and principles……….33
4.4 DDD for comparison of consumption………34
4.5 Principles for DDD assignment……….35
4.6 Drug utilization………..35
4.7 Definition of cost-minimization analysis………...36
ABBREVIATIONS
ALT Alanine Aminotransferase
Apo B-100 Apolipoprotein B – 100
AST Aspartate Aminotransferase
ATC Anatomical Therapeutic Chemical classification
CHD Coronary Heart Disease
CK Creatine Kinase
CMA Cost Minimisation Analysis
CRP C-reactive Protein
CVD Cardiovascular Disease
CYP Cytochrome P450
DDD Defined Daily Dose
FDA Food and Drug Administration
HDL-C High-Density Lipoprotein Cholesterol HMG-CoA 3-hydroxy-3-methylglutaryl Coenzyme A IDL Intermediate Density Lipoprotein
LDL-C Low-Density Lipoprotein Cholesterol MCID Minimally Clinically Important Difference
MI Myocardial Infarction
NCEP ATP III National Cholesterol Education Program Adult Treatment Panel III NICE National Institute for Health and Clinical Excellence
PP Pyrophosphate
TC Total Cholesterol
ULN Upper Limit of Normal
VLDL Very Low Density Lipoprotein
1. INTRODUCTION
Irrational use of medicines is a major problem worldwide. It is estimated that half of all medicines are inappropriately prescribed, dispensed or soled and that half of all patients fail to take their medicines properly. The overuse, underuse or misuse of medicines results in wastage of scare resources and widespread health hazards [1].
Despite widespread prevention programs to reduce risk, cardiovascular disease (CVD) – which includes coronary heart disease (CHD), stroke, and peripheral arterial disease – remains the leading cause of death worldwide. According to World Health Organization (WHO) statistics, more then 16 million people die of CVD each year. Furthermore, the prevalence of CHD is increasing as population’s age and, as unhealthy lifestyles is adopted [2].
Low and middle-income countries are experiencing an increase in CHD risk factors that is expected to dramatically increase their burden of CVD, as well as associated treatment and lost productivity costs. According to Lithuanian Heath Information Centre, 2006 CHD contributed more then 15,000 (about 54%) of all deaths in Lithuania. The highest mortality rate associated with CHD was among age group of 65 years and more and was responsible for 39,2% of deaths [3].
Three risk factors in particular – elevated cholesterol, smoking, and high blood pressure – or combinations of these factors are responsible for more than 75% of all CVD worldwide [2]. There is conclusive evidence that lowering low density lipoprotein cholesterol (LDL-C) levels reduces the risk of CHD and disease-related morbidity and mortality. Also both European and US guidelines recommend the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, as first-line therapy for dyslipidemia and specify target LDL-C levels [4].
Statins treatment reduces the risk of atherosclerotic cardiovascular complications in both primary and secondary prevention settings. Statin therapy as primary prevention may approach high cost-effectiveness and is recommended as a part of the management strategy for the primary prevention for adults who have a 20 percent or greater 10-year risk of developing CVD [5]. Demand for statins is already rising, and wider acceptance of the benefits of these lipid-lowering interventions will increase demand further.
CHD cost the healthcare system of Lithuania under €41 million in 2003. The major component of health expenditures was inpatient care, which accounted for €25 million of healthcare costs, followed by pharmaceutical expenditures, which represented €11 million of total healthcare costs [6].
The indirect costs in primary CHD prevention are substantial, and should also be considered. CHD is a significant cause of morbidity and can have a major impact on quality of life. CHD has estimated to be the leading cause of disability in Europe, accounting for 9.7% of total disability-adjusted life years [2]. Indirect cost is usually expressed at lost productivity due to disability or premature mortality. Of the total cost of CHD in Lithuania about 50% of costs were due to direct healthcare costs, 36% to productivity losses and 14% to the informal care of people with CHD in 2003 [3]. Incorporating indirect costs of CHD offset by statin therapy into cost-effectiveness analysis reveals that statin therapy is highly cost-effective and can even lead to cost savings; cost savings are realized when medication-associated costs are completely offset by savings due to avoid disease.
But there is evidence that eligible patients are not being adequately treated, possibly due to failure to identify patients who are at risk, or due to use of insufficiently potent statins. In order to optimize treatment, patients should be regularly monitored and statins titrated until an adequate level of lipid lowering is achieved [7].
The increase in the treatment of hyperlipidemia with statins has resulted in an increase in the costs of drug therapy. Finding ways to reach the appropriate endpoints of treating hyperlipidemia and managing the cost is critical to all health care systems. Rational use of statins represents an important and growing part of cardiovascular therapy [8].
Relevance and novelty of this work
Statins therapy is a lifelong treatment and benefits occur well in the future. The use of statins worldwide has grown dramatically in the last few years. Hence, to date no studies have been published that investigates the pharmacoeconomical and pharmacoepidemiological analysis of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) consumption in Lithuania.
2. STATINS FOR THE PREVENTION AND TREATMENT OF CARDIOVASCULAR DISEASE
2.1 About cholesterol
High blood cholesterol is a major modifiable risk factor for CHD. Every 10% reduction in total cholesterol (TC) decreases the risk of coronary death by 15%. Hence, cholesterol-lowering treatments, including statins, are recommended for an ever-widening section of the population. [9]
In humans, cholesterol serves 5 main functions:
1. Cholesterol is used by the body to manufacture steroids, or cortisone-like hormones, including the sex hormones. Combined, these hormones control a myriad of bodily functions.
2. Cholesterol helps the liver produce bile acids. These acids are essential for digestion of fats and ridding the body of waste.
3. Cholesterol acts to interlock “lipid molecules”, which stabilize cell membranes. Therefore, cholesterol is a vital building block for all bodily tissues.
4. Most notably, cholesterol is an essential part of the myelin sheath. The myelin sheath, similar to the coating on copper wire, ensures that the brain functions properly by aiding the passage of electrical impulses. Without the myelin sheath, it is difficult to focus and we can lose memory. 5. And finally, cholesterol has beneficial effects on the immune system. Men with high cholesterol
have stronger immune systems than those with low cholesterol, as can be seen by the fact that they have more lymphocytes, total T-cells, helper T-cells and CD8+ cells. Further, many strains of bacteria, which cause us to get sick, are almost totally inactivated by LDL-C. [10]
Cholesterol is an important lipid present in all cell membranes. In excess, it accumulates in deposits of atherosclerotic plaque on the walls of blood vessels, leading to restrictions and interruptions of the circulation that can result in angina, heart attacks, and death. Populations with low cholesterol levels have less CHD than with higher cholesterol levels, but individuals moving from a low level population to a high level population show increases in their cholesterol levels and rates of CHD. [11]
In the bloodstream, cholesterol and triglycerides circulate as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into four main classes:
• High density lipoproteins (HDL): HDL-C accounts for 20-30% of total serum cholesterol. Levels are inversely correlated with CHD risk, which may be due to a protective effect, or to the fact that low HDL-C levels are associated with other atherogenic factors. It is sometimes referred to as “good” cholesterol.
• Very low density lipoproteins (VLDL): These are rich in triglycerides, but account for 10-15% of total serum cholesterol. Partially degraded VLDL (VLDL remnants) is enriched with cholesterol, and seems to be atherogenic.
• Chylomicrons: These are rich in triglycerides, and partially degraded chylomicron remnants are probably atherogenic.
TC is usually subdivided into either HDL-C and LDL-C, or HDL-C and non- HDL-C. [12]
Most cholesterol in the body is made by the liver from a wide variety of foods, but especially from saturated fats, such as those found in animal products. Cholesterol and triglycerides synthesized in the liver are incorporated into VLDL and secreted into the circulation for delivery to peripheral tissues. Triglycerides are removed by the action of lipases, and in a series of steps, the modified VLDL is transformed first into intermediate-density lipoproteins (IDL) and then into cholesterol-rich LDL. IDL and LDL are removed from the circulation mainly by high affinity ApoB/E receptors, which are expressed to the greatest extent on liver cells. HDL is hypothesized to participate in the reverse transport of cholesterol from tissues back to the liver.
A number of diseases are associated with non-optimal cholesterol levels. Epidemiologic, experimental, and clinical studies have established that high LDL-C, low HDL-C, and high plasma triglycerides promote human atherosclerosis and are risk factors for developing CVD. In contrast, higher HDL-C is associated with decreased cardiovascular risk.[13]
2.2 CVD: etiology, pathology and prognosis
CVD accounts for much morbidity and mortality in developed countries and is becoming increasingly important in less developed regions. CVD is one of the main causes of disability and premature death (death in people aged under 75) throughout the world and contributes substantially to the escalating costs of health care. [14] At all ages, death rates are higher in men than in women. It may be due to differences between men and women in their intake of and response to dietary fat.
1. CHD
2. Transient ischemic attack and stroke 3. Peripheral arterial disease.
The underlying pathology is atherosclerosis, which develops over many years and is usually advanced by the time symptoms occur, generally in the middle age. Acute coronary and cerebrovascular events frequently occur suddenly, and are often fatal before medical care can be given. [11]
CHD is caused by the narrowing of the arteries that supply the heart, as a result of a gradual build-up of fatty material called atheroma. This can cause angina and myocardial infarction (MI) as well as other forms of chronic heart disease. [14]
CVD accounts for approximately half of all deaths and a large expenditure of health care resources. The cost of treating CVD accounts for ~10% to ~15% of total health care expenditures in developed countries. [15] Cardiovascular morbidity is a major contributor to the present global burden of disease and is an important part of western health budgets, particularly because of the related hospital charges for cardiovascular complications. Any intervention addressing the reduction of cardiovascular events and its hospitalization should be welcomed by health decision makers. [16]
Several risk factors for CVD have been identified. These include:
• Hyperlipidemia (including hypercholesterolaemia, familial hypercholesterolaemia and familial combined hyperlipidaemia);
• Hyperapobetalipoproteinaemia; • Cigarette smoking;
• Hypertension; • Diabetes mellitus;
• Familial history of premature CHD; • Physical inactivity;
• Obesity; • Male gender; • Ethnicity; • Increasing age.
risk factors has been shown to reduce mortality and morbidity in people with diagnosed or undiagnosed CVD also to reduce premature death in people with established CVD as well as in those who are at high cardiovascular risk due to one or more risk factors. [14]
The debilitating and often fatal complications of CVD are usually seen in middle-aged or elderly men and women. However, CHD is often undiagnosed or misdiagnosed in the elderly. Angina pectoris is common in this age group, but its manifestation is often atypical and is associated with dyspnea, worsening heart failure, and non-Q-wave MI. Many elderly people may not experience exertional angina because they are generally less physically active and tend to have a sedentary lifestyle. Clinicians may misdiagnose angina in the elderly as peptic ulcer disease or degenerative joint disease. Acute MI can also be missed because symptoms in the older patient may be atypical or vague. Acute MI should be suspected when patients exhibit unexplained behaviour changes, acute signs or cerebral insufficiency, or dyspnea. More than one third of MI’s in the elderly may be unrecognized or clinically silent.
However, atherosclerosis – the main pathological process leading to coronary artery disease, cerebral artery disease and peripheral artery disease – begins early in life and progresses gradually through adolescence and early adulthood. It is usually asymptomatic for a long period.
The rate of progression of atherosclerosis is influenced by cardiovascular risk factors: tobacco use, an unhealthy diet and physical inactivity (which together result in obesity), hypertension, dyslipidemia and diabetes. Continuing exposure to these risk factors leads to further progression of atherosclerosis, resulting in unstable atherosclerotic plaques, narrowing of blood vessels and obstruction of blood flow to vital organs, such as the heart and the brain. Given this continuum of risk exposure and disease, the division of prevention of CVD into primary, secondary and tertiary prevention is arbitrary, but may be useful for development of services by different parts of the health care system. The concept of a specific threshold for hypertension and hyperlipidemia is also based on an arbitrary dichotomy.
In many patients, lipid disorders can be managed with lifestyle changes. Lifestyle measures are often associated with additional benefits, such as decreased blood pressure and improved glucose tolerance, and they should be emphasized for all patients. Although lifestyle has a strong influence on CHD rates, dyslipidemia with a strong genetic component is frequently not normalized by lifestyle changes. [12]
In 2004, the Department of Health stated that 1.8 million people (over 2% of the population) were currently receiving statin therapy for primary and secondary prevention of CVD. However, many patients, who would benefit are currently untreated. Less than half of patients with CHD were on a statin or other lipid-lowering drug and a significant proportion of those were on suboptimal doses. [14]
2.3 Cholesterol-lowering therapy: getting statins
For the last 20 years or more, lowering the LDL components of total serum cholesterol has been the principal focus in cholesterol management. Ever more powerful HMG-Co A reductase inhibitors (statins) captured attention in their availability to lower LDL-C.
Lovastatin was the first 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor approved by the U.S. Food and Drug Administration (FDA) on August 13, 1987, reduced LDL-C by an average 30% at the 40 mg daily dose and by 40% when taken twice daily (80 mg daily dose) (Table 1). [18]
Table 1 An average effects of statins on LDL-C and HDL-C at maximum daily dose Generic Name Brand Name FDA Approval Maximum
Daily Dose
LDL-C Reduction (%)*
HDL-C Elevation (%) **
Lovastatin Mevacor Aug.13, 1987 80 mg -40% +8%
Pravastatin Pravachol Oct. 31, 1991 80 mg -37% +3%
Simvastatin Zocor Dec. 23, 1991 80 mg -47% +8%
Fluvastatin Lescol XL Dec. 31, 1993 80 mg -35% +7%
Atorvastatin Lipitor Dec. 17, 1996 80 mg -60% +5%
Cerivastatin# Baycol Jul. 21, 2000 0.8 mg -42% +10%
Rosuvastatin Crestor Aug. 13, 2003 40 mg -63% +10%
* Mean LDL-C reduction at maximum daily dose **Mean HDL-C elevation at maximum daily dose
Five statins are now available in Lithuanian drug market: pravastatin, simvastatin, fluvastatin, atorvastatin and rosuvastatin. [20]
There are three generations of HMG-CoA reductase inhibitors. Each generation has slight differences, but all are selectively targeted to HMG-CoA reductase in the liver. Lovastatin and simvastatin are first-generation HMG-CoA reductase inhibitors. Pravastatin is a second-generation HMG-CoA reductase inhibitor and fluvastatin, cerivastatin, atorvastatin and rosuvastatin are third-generation HMG-CoA reductase inhibitors. [19]
Lovastatin and pravastatin are natural statins isolated from a strain of Aspergillus terreus; simvastatin is a semi-synthetic statin based on lovastatin; and atorvastatin, fluvastatin, and rosuvastatin, are fully synthetic lipid lowering agents. Pravastatin, simvastatin, atorvastatin and rosuvastatin are available as immediate-release forms. Fluvastatin and lovastatin are available in extended-release as well as immediate-release forms. [21]
2.3.1 Dosage
The dose of the statin should be based mainly on target lipid levels, e.g. LDL-C. Generally, the lowest dose that produces and maintains the desired levels should be used. Additional factors such as alcohol intake and concurrent drug therapy may influence the initial dose. Advanced age is generally not a factor in determining initial doses of statins, although some have recommended a lower initial dose as a precaution. [22]
Usual starting doses are rosuvastatin 10 mg, atorvastatin 10 mg, pravastatin 40 mg, and 20 mg for other statins. The maximum daily dose for rosuvastatin is 40 mg. For all other statins, the maximum FDA-approved daily dose is 80 mg. For lovastatin and pravastatin, the maximum dose usually is prescribed as 40 mg twice a day (Table 2). [21]
Table 2 Doses of statins that result in similar percent reduction in LDL-C
Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Rosuvastatin
Statins are usually taken in one daily dose in the evening, presumably to coincide with cholesterol synthesis, which is thought to peak in the early morning hours. Maximum therapeutic benefit is usually seen after 4 weeks of therapy at a given dose. Dose adjustments should be made at intervals of no less than 4 weeks.
Depending on the statin used, patients should take this class of medication consistently with or without food. Under fasting conditions, lovastatin levels are ~2/3 of those found when given immediately after meals; therefore, it is recommended that patients take lovastatin with meals; simvastatin, fluvastatin, pravastatin, atorvastatin and rosuvastatin may be taken without regard to meals. [22]
2.3.2 Effectiveness
The effectiveness of any lipid-lowering treatment depends critically on the compliance of patients and can be expressed in a number of ways.
When effectiveness is expressed as percent reduction in LDL-C and cost as statin price, increasing the efficacy (the effect per unit dose) decreases the cost-effectiveness ratio and, when greater LDL-C lowering is required (as is the case with patients with CHD or CHD-equivalent risk), the statins with the greatest efficacy have the lowest (most favourable) cost-effectiveness ratios. If limited LDL-C lowering is required (as may be the case for some low-risk patients), drug price may be more important factor.
The same relationships between the cost-effectiveness ratio, statin efficacy and price are also seen when effectiveness is expressed as the proportion of patients reaching LDL-C goal. The inverse relationship between statin efficacy and the cost-effectiveness ratio holds up under the circumstances of statin titration to treatment goal and the inclusion of all related treatment costs.
When effectiveness is expressed in terms of life years saved and all long-term medical costs are taken into account, the incremental cost-effectiveness ratio decreases as the risk of CHD increases. For patients with pre-existing CHD or CHD-equivalent risk of coronary events, the cost-effectiveness ratio of statins as a class compares favourably with generally accepted medical treatments. [9]
The effectiveness of statins increases with dosage, but efficacy is a fixed property for each statin. There are 2 ways of increasing the effectiveness: (a) increasing the dose of a given statin or (b) using the same dose of another statin with greater efficacy. There are limits, however, to the extent to which the effectiveness of statins with relatively low efficacy can be increased by raising the dose. As an example, the effectiveness of pravastatin 80 mg (measured as percent reduction in LDL-C) is 65% greater than that of pravastatin 10 mg but still less than that of rosuvastatin 5 mg and considerably less than that of higher dosages of statins with greater efficacy. Although it has been argued that the statins are clinically interchangeable,the differences in efficacy and price have important consequences in the determination of cost effectiveness of statins. [9]
Intensive-dose statin therapy that is associated with a reduced risk for important cardiovascular events compared with moderate-dose statin therapy is also associated with an increased risk for statin-induced adverse events. Hence, moderate-dose statin therapy may be the most appropriate choice for achieving cardiovascular risk reduction in the majority of individuals, whereas intensive-dose statin therapy may be reserved for those at highest risk. [24]
Instead of statins side effects, one might lose sight of the fact that these drugs are lifesaving medications. To see the comparison more clearly, both risk and benefit can be expressed in terms of mortality change per person-year of statin treatment. In comparison, the risks of permanent organ damage resulting from statin treatment are very small. The significant risks pertain to rhabdomyolysis and myopathy (although recovery is the usual course) and perhaps to peripheral nerve damage (most patients also recover). Therefore, when the benefits of averting infarction of the myocardium and brain are considered, the risk– benefit ratio for permanent organ damage with appropriately administered statin treatment is very low. [25]
2.3.3 Labelled indications for statins use
According to NCEP ATPIII (National Cholesterol Education Program Adult Treatment Panel III) guidelines, therapy with lipid-altering agents should be a component of multiple-risk-factor intervention in individuals at increased risk for CHD due to hypercholesterolemia. The two major modalities of LDL-lowering therapy are therapeutic lifestyle changes and drug therapy. [13]
measures are inadequate; also as an adjunct to diet for the treatment of patients with elevated serum triglycerides (Table 3).
Statins are indicated for primary and secondary prevention of coronary events to reduce:
• Cardiovascular mortality and morbidity in people with manifest atherosclerotic CVD or diabetes mellitus (with either normal or increased cholesterol levels), as an adjunct to correction of other risk factors and other cardioprotective therapy;
• Cardiovascular mortality and morbidity in people with a history of MI or unstable angina and with either normal or increased cholesterol levels, as an adjunct to correction of other risk factors;
• Post-transplantation hyperlipidemia in people receiving immunosuppressive therapy following solid organ transplantation;
• The risk of stroke and stroke/transient ischemic attack;
• Coronary events after percutaneous coronary intervention in people with CHD.
Statins are also indicated for the increase of HDL-C in people with primary hypercholesterolemia and mixed dyslipidemia (XL formulations only). [5] [13] [26]
Table 3 Lipid-lowering effects of statins
Indication Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Rosuvastatin
Hypercholesterolemia + + + + + + Hyperlipoproteinemia + + + + + + Hypertrigliceridemia + + + + + Atherosclerosis + + + MI + + + + Stroke + + + Revascularization procedures + + + + + Unstable angina + +
2.3.4 How do statins work?
The body can synthesize up to 1 g of cholesterol per day, while 20-40 mg per day is absorbed from food, and serum cholesterol levels correlate with saturated fat intake much more closely than with dietary cholesterol intake. [10]
HMG-CoA reductase inhibitors are the most effective class of drugs, recommended as first-line agents for patients who require drug therapy to reduce serum LDL-C concentrations. [5]
Cholesterol is synthesized from acetyl-CoA in virtually all human cells, but primarily in hepatocytes. All CoA reductase inhibitors target hepatocytes and competitively inhibit HMG-CoA reductase, the enzyme that converts HMG-HMG-CoA into mevalonate, a precursor of cholesterol (Figure 1). [27] The conversion of HMG-CoA to mevalonate is the rate-limiting step in de novo cholesterol synthesis. The mevalonate pathway branches out before the synthesis of squalene and cholesterol. Other biologically important products are dolichols (involved in lipoprotein synthesis), ubiquinone, and the isoprenoids, farnesyl- pyrophosphate (PP) and geranylgeranyl-PP.
Figure 1 Mevalonate pathway
Mevalonate, whose synthesis is blocked by HMG-CoA reductase inhibitors, is important not only in cholesterol synthesis, but also in production of ubiquinone (coenzyme Q 10) in the muscle cell. Ubiquinone is utilized by the electron transport chain for ATP synthesis. Thus, HMG-CoA reductase inhibitors can lead to interference with ATP synthesis and this may be the mechanism of muscle injury. [19]
In vitro and in vivo studies have shoved that statins produces their lipid-modifying effects in
two ways. First, they increase the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Statins alter the conformation of the enzyme when they bind to its active site. This prevents HMG-CoA reductase from attaining a functional structure. The change in conformation at the active site makes these drugs very effective and specific. Binding of statins to HMG-CoA reductase is reversible, and their affinity for the enzyme is in the nanomolar range, as compared to the natural substrate, which has micromolar affinity. [29]
Secondary mechanisms by which statins may reduce levels of atherogenic lipoproteins include inhibition of hepatic synthesis of Apo B-100 and a reduction in the synthesis and secretion of VLDL, which reduces the total number of VLDL and LDL particles. [13] [27]
Reduced cholesterol synthesis results in lower levels of hepatic cholesterol, and up-regulation of LDL receptor activity in the liver. There is greater uptake of serum LDL and other non-HDL particles by the LDL receptors, leading to lower levels of TC and non-HDL-C in the circulation. All statins reduce LDL-C non-liniarly, dose-dependent, and after administration of a single daily dose. Efficacy on triglyceridereduction parallels LDL-C reduction. [29] Statins also raise HDL-C levels by about 5%, but the mechanism is unknown, and how much this contributes to the overall reduction in CHD risk is uncertain. Evidence is also accumulating for effects of statins that are independent of cholesterol lowering. [10]
2.3.5 Non-lipid effects of statins
Endothelial dysfunction is an early critical component of organ injury after acute events such as MI, ischemic stroke and hemorrhage, and in chronic disease states such as diabetes and hypercholesterolemia. It is a good prognostic indicator for cardiac events and mortality, so an important target for intervention. [10]
Statins are beneficial both in the primary and secondary prevention of atherosclerotic vascular disease and acute events in a broad spectrum of patient subgroups. However, the observed clinical benefit with statin therapy is much greater than expected through the reduction of cholesterol levels alone. Accumulating evidence suggest that statins in particular have number of properties beyond LDL-lowering that may contribute to their clinical benefits. These properties, independent of lipid LDL-lowering, often referred to as pleiotropic effects. [30]
Pleiotropic effects occur soon after initiation of statin therapy, within hours or days, as opposed to the longer time required for the cholesterol-lowering effects to become evident. The early onset of action as well as the plaque-stabilizing effects of statins could explain in part their benefit in acute coronary syndromes. [2]
It appears that hydrophilic statins, such as pravastatin and rosuvastatin, exert similar effects on the vasculature as do lipophilic statins, including atorvastatin and cerivastatin, which would be expected to have greater cell penetration. The statins exert their action through their ability to bind more potently to HMG-CoA reductase than HMG-CoA. However, differences exist between statins with respect to their ability to bind HMG-CoA, their potency and whether they are predominantly lipophilic or hydrophilic, and this may influence their pleiotropic effects which include:
1. Improved endothelial function through increased NO production, due to upregulation of endothelial nitric oxide synthase;
2. Anti-inflammatory effects due to reduction of acute phase proteins, including C-reactive protein (CRP), inflammatory cytokines and cell adhesion molecules;
3. Antioxidant effects due to scavenging of superoxide and inhibition of isoprenoids (superoxide generators);
4. Antithrombotic effects due to a shift in the fibrinolytic balance towards fibrinolysis and reduced platelet aggregation;
5. Stabilization of atherosclerotic plaque;
6. Antiproliferative effects, due to inhibition of smooth muscle cell proliferation. [31]
risk. Clinical studies show that statins lower plasma levels of hs-CRP, a measure of inflammation, and may have greater beneficial effects in dyslipidemic subjects who have evidence of chronic inflammation. Statins exhibit antioxidant properties, which explain their ability to increase the resistance of LDL to oxidation and lower plasma concentrations of oxidized LDL. This effect becomes important with the recent finding that the severity of acute coronary syndromes is related to plasma (and atheroma) levels of oxidized LDL. Statins appears to contribute to the stabilization of vulnerable plaques in humans through their anticoagulant and profybrinolytic properties.
Statins may also exhibit a wide variety of actions other than antiatherosclerotic effects. Recent observational data documented a potential association between statin use and improvement of fracture risk in osteoporosis. Despite the lack of randomized trials, epidemiological and limited clinical data suggested that statins might retard the pathogenesis of Alzheimer's disease. Observational data indicated that the progression of aortic stenosis and valvular calcification might be delayed in statin users. In addition, the deterioration of congestive heart failure may be delayed with statins via anti-inflammatory, vascular endothelial and antiatherosclerotic actions. Furthermore, preliminary clinical studies suggested that, by their immunosuppressive actions statins might reduce the incidence of rejection following organ transplantation. Currently, there is not enough evidence to prescribe therapy for such patients. However, ongoing studies are exploring the role of statin therapy for these new indications. [32]
2.3.6 Pharmacokinetics of HMG-CoA reductase inhibitors
All of the statins are rapidly absorbed after oral administration, with tmax usually reached within
Table 4 Pharmacokinetics of statins
Drug Bioavailability Excre- tion T1/2 (h) Major metabolites Protein binding Effects of renal/ hepatic impairment Lovastatin ~35% absorbed; extensive first-pass metabolism; <5% of oral dose reaches
general circulation 10% (urine) 83% (faeces) 3 to 4 Betahydroxyacid; 6'- hydroxy derivative; 2 additional metabolites > 95% Increased plasma concentration with severe renal disease
Pravastatin 34% absorbed; absolute bioavailability 17%; extensive first-pass metabolism; ~20% (urine) 70% (faeces) 1.8 Major degradation product: 3 - hydroxyl isomeric metabolite ~50% Initial doses decreased in severe renal impairment Simvastatin 60% to 80% absorbed; extensive first-pass metabolism; <5% of oral dose reaches
general circulation 13% (urine) 60% (faeces) 3 Betahydroxyacid; 6'- hydroxy, 6'- hydroxymethyl, 6'-exomethylene derivatives ~95% Increased plasma concentration with hepatic and severe renal insufficiency Fluvastatin 98% absorbed; absolute bioavailability 24%; extensive first-pass metabolism <6% (urine) ~90% (faeces) < 1 Hydroxylated metabolites (active, do not circulate systemically) 98% Potential drug accumulation with hepatic insufficiency Atorvastatin ~14% absolute bioavailability; first-pass metabolism <2% (urine) ~14 Metabolized to ortho- and parahydroxylated derivatives (active) > 98%
Plasma levels not affected by renal disease but markedly increased with chronic alcoholic liver disease. Rosuvastatin 20% absorbed; not extensive first-pass metabolism 10% (urine) 90% (faeces) 19 N-desmethyl derivative 88% Increased plasma concentration with severe renal disease
(CrCl<30ml/min)
All currently available statins show very low systemic bioavailability due to an extensive first pass metabolism at the intestinal and/or hepatic level. This is an advantageous characteristic because the liver is the target organ for statins; moreover, the lipophilic nature of several of the statins means that a lower bioavailability may reduce the risk of systemic side-effects. [33]
All of the statins apart from pravastatin exhibit a high degree of binding to plasma proteins, primarily to albumin. Consequently, the systemic concentration of the pharmacologically active form of the free statin portion is generally low and, as the hepatic uptake of the statin is usually high drug interactions secondary to the presence of high plasma drug concentrations are unlikely. [22]
One of the main aims of developing an extended-release formulation of fluvastatin was to inhibit the hepatic synthesis of cholesterol over a prolonged period. In addition, it permits continuous and prolonged hepatic exposure to the drug without saturating the capacity for liver uptake. The low systemic exposure of extended-release fluvastatin is expected to translate into improved tolerability, particularly for the musculature, and a lower potential for drug interactions than the immediate-release formulation. It should be noted, however, that the rapid tmax and short plasma half-life of fluvastatin
mean that extended-release formulations offer a marked improvement in pharmacokinetic properties compared with immediate-release formulations. Nevertheless, an extended-release formulation of lovastatin has also been developed in order to provide a smoother plasma concentration-time profile, a lower maximum plasma concentration and a prolonged half-life compared with that of immediate-release lovastatin. [33]
2.3.7 Metabolism
Since statins have a different metabolic pathway in the liver, there are bound to be differences between statins in term of myopathic adverse effects.
Statins are metabolized by the cytochrome P450 system. CYP3A4 is one of the major isoensymes of the CYP group. This isoenzyme metabolizes some HMG-CoA reductase inhibitors, such as lovastatin, simvastatin and atorvastatin. Fluvastatin is metabolized by CYP2C9 and may interact with CYP2C9 inhibitors. Pravastatin has minimal metabolism by CYP3A4 and is primarily cleared by the kidneys. Rosuvastatin is not extensively metabolized; approximately 10% of radio-labelled dose is recovered as metabolite by CYP2C9. [13]
Statins and their metabolites are eliminated mainly by biliary excretion and to a much lesser extent by the kidneys. Renal impairment may involve initial lower doses for lovastatin, pravastatin, and rosuvastatin. Atorvastatin and fluvastatin do not require any dose adjustment. Statin therapy is not recommended in patients with active liver disease.
cytochrome P450 system, there is accumulation of both substrates, which increases the potential for adverse drug reactions. This is the mechanism by which concurrent use of some drugs with statins induces adverse reactions. [34]
2.3.8 Safety issues with statin therapy
Adverse effects:
Although the statins are generally well tolerated when used at moderate doses, there are well-described adverse events associated with their use. The risk of a statin-associated adverse event while receiving statin therapy has been reported to be increased by 40% relative to placebo. [24]
Adverse reactions caused by statins usually have been mild and transient: they include headache, paraesthesia, dizziness, and gastrointestinal effects including abdominal pain, flatulence, diarrhea, constipation, nausea and vomiting. Rash and hypersensitivity reactions (including angioedema and anaphylaxis) have been reported, but are rare. [13] [14]
However, some of the adverse effects associated with statins are potentially very serious. Rare, but clinically important adverse effects are muscle effects (myalgia, myositis and myophaty), elevations in hepatic transaminases and peripheral neuropathy (Table 5).
Table 5 Potential adverse effects of statin therapy
Adverse effect Frequency, %
Myalgia 2 – 11 %
Headache, gastrointestinal effects including abdominal pain, flatulence, diarrhea,
constipation, nausea and vomiting, paraesthesia, insomnia, dizziness < 2 %
Elevated hepatic transaminases (AST and ALT) 0.5 -2.0 %
Muscle toxicity: • Myopathy • Rhabdomyolysis
0.1 – 0.5 % 0.04 – 0.2 %
The most common adverse effect, non-serious symptoms of myalgia, has been reported by some 2% to 11% of patients. Myalgia defined as creatine kinase (CK) increase to at least ten times the upper limits of normal (ULN) (>2000 U/L) accompanied by muscle pain or weakness. However, it should be noted that myalgia is a subjective symptom encountered even in patients receiving placebo during clinical trials. [33] Although this typically reversible effect is troublesome for patients, it may go unreported in many patients because of its self-limiting nature. Although symptoms may subside after drug discontinuation, symptoms frequently return on rechallenge (95% of patients have a return of symptoms when restarting therapy at the same dose). [24]
Elevated hepatic transaminases (AST and ALT) occur less frequently (0.5%-2.0% of patients) and are asymptomatic. Elevations of transaminase levels usually occur within the first 12 weeks of statin therapy and returns to normal with discontinuation therapy. Hepatotoxicity is dose-related: higher statin doses associated with a higher rate of liver enzyme abnormalities. It is recommended that liver function tests be performed before the initiation of statins, 6 and 12 weeks after initiation of therapy or increase in dose, and periodically, i.e., semi-annually thereafter. Liver enzyme changes generally occur in the first 3 months of treatment with atorvastatin, or fluvastatin and within 3-12 months of starting lovastatin. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. If an increase in ALT or AST > 3 times the ULN (>120 U/L) persists after a repeated test, dose should be reduced or statin discontinued.
Seriously adverse events such as clinically important myopathy and rhabdomyolysis also have been reported, but are considered rare (Table 5). Myopathy (also called myositis) is defined as any muscle symptom – pain, tenderness, or weakness – accompanied by a CK concentration greater than ten times the ULN for the particular laboratory. Rhabdomyolysis is severe myopathy involving muscle breakdown and the release of myoglobin into the blood stream, causing possible damage to the kidneys and other organs. Symptoms of rhabdomyolysis include generalized or specific myalgia, muscle tenderness, fever, nausea, vomiting, and dark urine. Rhabdomyolysis is usually diagnosed when CK concentration is greater than 40 times the ULN, or there is evidence of end organ damage (e.g., acute renal failure or worsened renal function), or both. If statin therapy is not discontinued, myopathy may result in rhabdomyolysis and acute renal failure. As clinicians begin to adopt an intensive strategy for their patients, the risk of these dose-related adverse effects is likely to increase. [24]
All medicines have adverse effects and these have to weigh up against the benefits. The more common side effects associated with statins would always be considered in making a decision about the relative risks and benefits of treatment or no treatment. [36]
Interaction:
A pharmacological interaction generally occurs when the pharmacokinetic or pharmacodynamic properties of one drug alter those of another drug. There is increasing evidence that the different statins differ both in their potential for interacting with other drugs and in their rates of adverse events.
In August 2001, Bayer Pharmaceutical Division voluntary withdrew cerivastatin, a synthetic statin, from the world market after the occurrence of 52 unexpected deaths from drug related rhabdomyolysis (31 in the USA and a further 21 worldwide). [14] On January 18, 2002, Bayer announced that the estimated number of worldwide deaths linked to cerivastatin had risen to 100. [37]
Rhabdomyolysis was 10 times more common with cerivastatin than the other approved statins, especially when used in high doses, in the elderly or, when taken along with fibrates (e.g. gemfibrozil, given for refractory hypercholesterolemia).
The probability of rhabdomyolysis (per day) in relation to cerivastatin dose in µg/kg body weight demonstrated that patients taking a higher daily dose (typically from the use of higher-strength products) were much more likely to develop rhabdomyolysis. The actual dose in µg/kg ranged from 1.9 µ g to 13.1 µ g, while the available strengths ranged from 0.2 mg to 0.8 mg. [38] It is likely that these high doses are sufficient to cause rhabdomyolysis even in the absence of concomitant fibrate therapy.
Many of the fatalities either had received the full dose of cerivastatin (0.8 mg per day) or were using the drug concomitantly with gemfibrozil: this drug-drug interaction was implicated in 12 of the 31 US fatalities. In addition, 385 non-fatal cases were reported among the estimated 700,000 cerivastatin users in the USA, and most of these required hospitalization. Bayer withdrew all dosages of cerivastatin throughout the world except in Japan where gemfibrozil is not available. [39]
Statins interact with a number of other medications. The risk of myopathy and rhabdomyolysis is dose related and is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. The development of myopathy is not simply a case of drug interaction, but the result of a complex interplay between the drug, disease, genetics and concomitant therapy. A number of other risk factors may also predispose patients to myopathy in the absence of statin therapy; these include increased age, female gender, renal or hepatic disease, diabetes, hypothyroidism, debilitated status, surgery, trauma, excessive alcohol intake and heavy exercise. [33]
telithromycin, HIV protease inhibitors (indinivir, ritonavir, amprenavir and other), delavirdine, itraconazole, fluconazole, ketoconazole, nefazodone, or large quantities of grapefruit juice). HMG-CoA reductase inhibitors are the substrates of CYP3A4. When HMG-CoA reductase inhibitors are used with the potent inhibitors of CYP3A4, elevated plasma levels of HMG-CoA reductase inhibitory activity can increase the risk of myopathy and rhabdomyolysis, particular with higher doses of HMG-CoA reductase inhibitors.
The risk of myopathy is also increased by the following lipid-lowering drugs: gemfibrozil, other fibrates, and niacin. With gemfibrozil, the risk is increased to such an extent that gemfibrozil and statins should not be used concomitantly. The concomitant use of statins with other lipid-lowering drugs should be undertaken with caution, and generally under specialist supervision.
The risk of myopathy and rhabdomyolysis is increased by concomitant administration of cyclosporine, danazol, amiodarone, verapamil, coumarin anticoagulants (warfarin), propranolol, digoxin, and oral hypoglycemic agents (glipizide), particular with higher doses of HMG-CoA reductase inhibitors.
In addition, because some statins (particularly atorvastatin and simvastatin) are metabolized by CYP3A4, concomitant use of potent inhibitors of this enzyme (e.g. azole antifungal agents and HIV protease inhibitors) may increase plasma levels of those statins and thus increase the risk of side-effect such as rhabdomyolysis. The risk of serious myopathy is also increased when high doses of simvastatin are combined with less potent CYP3A4 inhibitors, including amiodarone, verapamil and diltiazem. Moreover, it appears that the consumption of even modest quantities of grapefruit juice can significantly increase exposure to simvastatin, thus increasing the risk of serious myopathy. Patients taking atorvastatin should also avoid drinking large quantities of grapefruit juice. Studies have shown that separation of grapefruit and statins by 12 hours may minimize the interaction. [22] These concerns do not apply to fluvastatin, which is metabolized by a different cytochrome P450 enzyme, or to pravastatin and rosuvastatin, which are not substantially metabolized by cytochrome P450. [14]
There is no specific treatment in the event of overdose; the patient should be treated symptomatically and supportive measures instituted as required. [13]
Contraindications:
Because they affect the liver, statins are contraindicated in patients with active liver disease or persistently abnormal liver function tests, and should be used with caution in patients with a history of liver disease or a high alcohol intake.
adequate thyroid replacement therapy may itself resolve any lipid abnormality. In patients with known hypersensitivity to these components the use of statins is also contraindicated. [14]
2.3.9 Recommendations for treatment
Choosing a statin
The HMG-CoA reductase inhibitors are an essential part of clinical lipid management aimed at prevention of atherosclerotic cardiovascular events. [25] Cholesterol-lowering is now recommended for a wide range of people at cardiovascular risk, including those with average and below-average lipid levels.This change is leading to increased statin use and to the use of more intensive regimens. [35]
Because of their effectiveness, tolerability and safety, the statins have become the first line agents for primary and secondary prevention of CHD in patients with elevated LDL-C levels. The benefits of statin treatment are independent of age, sex and cholesterol baseline. This has been taken to suggest that statins should be considered for everyone with an increased vascular risk irrespective of cholesterol level, moving away from the treatment of hyperlipidaemia per se. [41]
The choice of statin is usually based on the clinician’s judgment of the relative importance of three factors: evidence of beneficial clinical outcomes, efficacy for lowering LDL-C and cost. [42] The AHA (American Heart Association) recommends that physicians prescribe the lowest dose necessary to achieve the desired goals for the patient. The statin should be chosen specifically for each patient, taking into consideration the cholesterol-lowering goals, potential side effects and the patient's preferences. They also recommend that physicians considering using lower doses of statins for people who are at higher risk for myopathy (muscle weakness). [43]
NICE (National Institute for Health and Clinical Excellence) recommends initiating statin therapy with an effective drug of low acquisition cost. Regardless of which statin is chosen, it needs to be at a dose sufficient to achieve the cholesterol lowering targets and taken long-term as prescribed. [41]
Table 6 NCEP ATP III (2004) goals based on major risk factors a
Description 10-year risk of
coronary event LDL-C goal
LDL-C level at which to consider drug therapy CHD and CHD risk equivalents b >20% <100 mg/dL (<2.6 mmol/L); <70 mg/dL (1.8 mmol/L) as “therapeutic option” ≥130 (100-129, drug therapy optional) ≥2 Risk factors ≤20% <130 mg/dL (<3.4 mmol/L); <100 mg/dL (2.6 mmol/L) as “therapeutic option”
≥130 if 10-year risk of events = 10%-20%
≥160 if 10-year risk of events <10%
0-1 Risk factors <10% <160 mg/dL (<4.1 mmol/L) ≥190 (160-189, drug therapy optional)
a
Major risk factors (excluding LDL-C) that may modify LDL-C goals:
• Cigarette smoking
• Hypertension (blood pressure ≥140/90 mm Hg or use of an antihypertensive medication)
• Low HDL-C (<40 mg/dL)
• Family history of premature CHD (CHD in male first-degree relative <55 years; CHD in female first-degree relative <65 years)
• Age (men ≥45 years; women ≥55 years)
b
CHD risk equivalents include other forms of atherosclerotic disease, diabetes, and combinations of multiple risk factors conferring a 10-year risk of CHD of >20%.
For patients who require LDL-C reductions of up to 35% to meet their goal, any of the statins are effective. In patients requiring an LDL-C reduction of 35% to 50% to meet the NCEP goal, atorvastatin 20 mg or more, lovastatin 80 mg, rosuvastatin 10 mg or more, and simvastatin 20 mg or more daily are likely to meet the goal.
Atorvastatin, simvastatin and rosuvastatin are considered high potency statins because they can lower LDL cholesterol more than 40%. Among high-potency statins,
• Atorvastatin 80mg daily and rosuvastatin 20 mg or more reduced LDL cholesterol by 50% or more;
• Atorvastatin 80mg had a higher rate of some adverse effects (GI disturbance and transaminase elevation) than simvastatin 80mg daily in the trial in which the LDL-C lowering of atorvastatin was greater than of simvastatin;
The LDL-C treatment goal of 100 mg/dL or less may be unattainable for some patients with very high LDL-C levels. For such patients it is more practical to agree on an achievable goal instead of setting an unrealistic goal unrelated to the patient’s LDL-C level before treatment. [42]
There are different strategies for selecting an appropriate starting dose [41]:
• 'Evidence - based dose' strategy's rationale it that the starting dose should be that with the best evidence of efficacy.
• The 'titrate to target' strategy uses lower starting doses to minimize the risk of toxicity and avoid using an unnecessarily high dose in many individuals to reach treatment targets.
• Lower starting doses should be considered for people at increased risk of myopathy.
Candidates for receiving the maximum dose of high potency statins (atorvastatin, simvastatin and rosuvastatin) are [45]:
• CHD patients at very high risk (e.g. diabetes mellitus, metabolic syndrome, smokers), in whom the optional target LDL-C levels are <70 mg/dL and their pre-treatment levels are >150 mg/dL; • Any CHD patient with very high baseline LDL-C levels (>200 mg/dL) in whom an LDL-C
<100 mg/dL should be achieved.
Dose titration
The ability to achieve goal cholesterol levels has enormous implications for patients, clinicians, and health care systems. In the NCEP guidelines, the goal varies according to the patient’s risk of developing CHD-related events: patients with a high absolute CHD risk status have the most stringent guideline goal, requiring intensive LDL-C lowering therapy (Table 6). The latest update of the guidelines issued by the NCEP ATP III has recommended that a wider range of the population than previously considered eligible should benefit from lipid-lowering treatment. [7]
The NCEP recommends checking lipid levels every five years in patients without CHD risk factors and every one to two years in patients with CHD risk factors.In most persons, LDL-C and HDL-C levels are relatively stable over the long term. Much expense would be saved if individuals with healthy LDL-C and HDL-C levels were re-screened less often than is recommended or than is requested by some patients. [42]
often remain on the starting dose of statin, despite failing to reach lipid goals. Use of statins with greater efficacy in reducing LDL-C levels may treat more patients to goal using the starting dose, without the need for dose titration. [7]
However, statins’ high costs limit the scope of treatment: society wants the best returns for its investments in health. This asks for priority setting aided by economical analyses, commonly cost effectiveness analyses. As relative risk reduction is thought to be constant, benefits are largely determined by absolute risk of CHD. The question is, because of costs, at which level of risk, treatment is cost effective. Different levels are used worldwide, ranging from 20% to 30% year absolute risk of CHD. [46]
Cost-effectiveness assessment for treatment
Since 1994, numerous large clinical trials have shown that HMG-CoA reductase inhibitors significantly reduce the incidence of cardiovascular morbidity and mortality. Although the rate of statins use has risen in recent years, there is substantial unmet need for lipid-lowering. [47]
Saving lives with statins is increasingly one of the greatest pharmaceutical bargains available today. While universal adherence for all patients is a desirable goal, incremental efforts should focus on improving adherence and discontinuation rates in those high-risk populations who are the most likely to benefit from their use. [48]
NICE (January 2006) has recommended:
• Statin therapy is recommended for adults with clinical evidence of CVD.
• Statin therapy is recommended as a part pf the management strategy for the primary prevention of CVD for adults who have a 20% or greater 10-year risk of developing CVD. This level of CVD risk should be estimated using an appropriate risk calculator, or by clinical assessment for people for whom an appropriate risk calculator is not available (for example, older people, people with diabetes or people in high-risk ethnic groups).
• When the decision has been made to prescribe a statin, it’s recommended that therapy should usually be initiated with a drug with a low acquisition cost (taking into account required daily dose and product price per dose).
It is not easy to synthesize the available evidence on medication pricing, treatment costs, drug safety, potency, outcomes evidence, and epidemiology to derive appropriate and cost-effective treatment guidelines for hypercholesterolemic patients. Cost-effectiveness analyses that consider only narrow intermediate measures of clinical effectiveness to derive cost per percentage LDL-C reduction ignore many key issues.They simplify away many of the factors that should be considered by clinicians and health plans in attempting to obtain value for money spent on lipid therapy. [49]
Because of a number of available statins and their enormous costs, this class of drugs often undergoes formulary limitations, guidelines for use, and therapeutic conversions by medication use or pharmacy and therapeutic committees across managed care organizations or government health care systems. These systems often have a preferred statin with a substantially discounted contracted price. Contract price competitions include therapeutic conversions from one agent to another formulary alternative or other efforts to decrease costs associated with these agents. [50]
Despite the general effectiveness of statins, not all patients achieve LDL-C targets while receiving statin monotherapy, and there are differences in the LDL-C-lowering effects of individual statins. [51] Statin therapy is cost-effective when given in addition to dietary advice. The guidelines should allow statin therapy and dietary treatment to start at the same time without delay. Despite the mounting evidence on the value of statin therapy, long-term therapy with statins is still underused in patients with CHD. [52]
3. OBJECTIVE AND AIMS
Objective:
To evaluate the trends of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors’ (statins’) consumption in Lithuania during 2005 – 2007.
Aims:
1. To evaluate the pharmacokinetic and pharmacodynamic characteristics of statins and to compare them within the group.
2. To evaluate utilization of statins in Lithuania during 2005 – 2007 years by the means of the ATC/DDD methodology.
3. To compare statins consumption data in Lithuania with similar studies data in other countries.
4. MATERIAL AND METHODS
4.1 The purpose of the ATC/DDD system
The purpose of the ATC/DDD (Anatomical Therapeutic Chemical/Defined Daily Dose) 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. [53]
4.2 The ATC classification – structure and principles
Structure
In the 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.
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.
4.3 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. The 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 weigh) 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.
4.4 DDD for comparison of consumption
ATC/DDD system has been used since the early 1970s in drug utilization studies where it has been demonstrated to be suitable for national and international comparisons of drug utilization, for the evaluation of long term trends in drug use, for assessing the impact of certain events on drug use and for providing denominator data in investigations of drug safety. The ATC/DDD system can be used for collection of drug utilization statistics in a variety of settings and from a variety of sources.
Use of the ATC/DDD system allows standardisation of drug groupings and stable drug utilization metric to enable comparisons of drug use between countries, regions, and other health care settings, and to examine trends in drug use over time and in different settings.
The DDD is often a compromise based on a review of the available information about doses used in various countries. The DDD may even be a dose that is rarely prescribed, because it is an average of two or more commonly used dose sizes.
Drug utilization figures should preferably be presented as numbers of DDDs/1000 inhabitants/day or, when in-hospital drug use is considered, as DDDs per 100 bed days. For antiinfectives (or other drugs normally used in short periods), it is often considered most appropriate to present the figures as numbers of DDDs per inhabitant per year.
DDDs/1000 inhabitants/day
4.5 Principles for DDD assignment
DDDs for plain substances are normally based on monotherapy. Exceptions to this rule are given in the guidelines. A DDD will normally not be assigned for a substance before a product is approved and marketed in at least one country.
The assigned DDD is based on the following principles:
• The average adult dose used for the main indication as reflected by the ATC code. When the recommended dose refers to body weight, an adult is considered to be a person of 70 kg. It should be emphasized that even special pharmaceutical forms mainly intended for children (e.g. mixtures, suppositories) are assigned the DDD used for adults. Exceptions are made for some preparations mainly used by children, e.g. growth hormones and fluoride tablets.
• The maintenance dose is usually preferred when establishing the DDD. Some drugs are used in different initial doses but this is not reflected in the DDD.
• The treatment dose is generally used. If, however, prophylaxis is the main indication, this dose is used, e.g. for fluoride tablets (A01AA01) and some antimalarials.
• A DDD is usually established according to the declared content (strength) of the product. Various salts of a substance are usually not given different DDDs. Exceptions are described in the guidelines for the different ATC groups.
The DDD is nearly always a compromise based on a review of the available information including doses used in various countries when this information is available. The DDD is sometimes a dose that is rarely if ever prescribed, because it is an average of two or more commonly used dose sizes. [54]
4.6 Drug utilization
The principal aim of drug utilization research is to facilitate rational use of drugs in populations. For the individual patient rational use of a drug implies the prescription of a well-documented drug in an optimal dose on the right indication, with the correct information and at an affordable price. Without knowledge on how drugs are being prescribed and used, it is difficult to initiate a discussion on rational drug use and to suggest measures to change prescribing habits for the better. Information on the past performance of prescribers is the linchpin of any auditing system. [55]
• Sales data such as wholesale data at a national, regional or local level.
• Dispensing data either comprehensive or sampled. In many countries pharmacies are computerised 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 organisations. 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 hospitalisation, 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 organisations. 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 centres at regional, district or village level. [53]
4.7 Definition of cost-minimization analysis
