TITLE PAGE Social Pharmacy and Pharmacoeconomics Department of Organization and Management in Pharmacy Faculty of Pharmacy,Comenius University Statins

and Pharmacoeconomics Dimitriadis George Nikiforou Melpomeni 3rd Year Academic Year 2011/2012 Table of contents 1)Abstract 2)Introduction 3)Background/Description of intervation 4)Clinical effectiveness 5)Pharmacoeconomics of statin use 6)Conclusion 7)References ABSTRACT Objectives: To evaluate the clinical effectiveness and cost-effectiveness of statins for the primary and secondary prevention of cardiovascular events in adults with, or at risk of, coronary heart disease (CHD). Review methods: A review was undertaken to identify and evaluate all literature relating to the clinical and cost effectiveness of statins in the primary and secondary prevention of CHD and cardiovascular disease (CVD). A Markov model was developed to explore the costs and health outcomes associated with a lifetime of statin treatment. Conclusions:The results of the economic modelling show that statin therapy in secondary prevention is likely to be considered cost-effective. In primary prevention, the cost-effectiveness ratios are dependent on the level of CHD risk and age, but the results for the CVD analyses offer support for the more aggressive treatment recommendation.

Introduction:
Cardiovascular disease is one of the major causes of premature death and the three major manifestations of CVD are: coronary heart disease (CHD), including myocardial infarction (MI, heart attack) and angina cerebrovascular disease [transient ischaemic attack (TIA) and stroke] peripheral arterial disease (obstruction of the arteries carrying blood to the legs or, less commonly, the arms). Several risk factors for CHD have been identified these include hyperlipidaemia. Some of these risk factors (e.g. smoking, obesity and hypertension) can be modified, treated or controlled. Others (e.g. age, gender and ethnicity) cannot. CHD risk can be reduced by cholesterol lowering, changes in lifestyle, such as smoking cessation, exercise and the use of cholesterol-lowering diets, along with non-cholesterol drug treatments, including aspirin and antihypertensives. The cost-effectiveness of statins must be seen in the context of these other interventions.

MAIN TEXT

Intervention
Statins act to lower cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, an enzyme involved in cholesterol synthesis, particularly in the liver.49 Inhibition of HMG CoA reductase lowers LDL-C levels by slowing down the production of cholesterol and increasing the livers ability to remove the LDL-C that is already in the blood.50 Because the body makes more cholesterol at night than during the day, it is recommended that some statins are taken in the evening.Statins are used both for the secondary prevention of coronary and cardiovascular events in patients with CHD (including a

history of angina or AMI),peripheral arterial disease or a history of stroke,and for primary prevention in patients who are at increased risk of coronary events because of factors such as smoking, hypertension and diabetes mellitus. Five statins are currently licensed for use: atorvastatin(licensed indication-Primary hypercholesterolaemia,heterozygous or homozygous familial

hypercholesterolaemia, mixed dyslipidaemia) fluvastatin(Primary hypercholesterolaemia or mixed dyslipidaemia; primary hypercholesterolaemia and CHD; CHD and prior PCI) pravastatin(Primary hypercholesterolaemia or mixed dyslipidaemia; moderate or severe hypercholesterolaemia and high risk of a first CV event; MI or unstable angina; immunosuppressive therapy following solid organ transplantation) rosuvastatin(Hypercholesterolaemia/dyslipidaemia) simvastatin(Primary hypercholesterolaemia or mixed dyslipidaemia; homozygous familial hypercholesterolaemia, atherosclerotic cardiovascular disease or diabetes mellitus) Indications for Statins: Primary Prevention of CAD:The effectiveness of drug treatment for lipid disorders in patients with no history of CAD has been controversial. Earlier reviews cautioned against drug treatment in patients with low to moderate risk of death from CAD because of possible increases in all-cause mortality with treatment. A more recent meta-analysis found that CAD events and all-cause mortality were reduced in primary prevention populations.

Secondary Prevention of CAD: Several trials using statins have also demonstrated a benefit in the secondary prevention of CAD, both in terms of retardation of the progression of signs of coronary atherosclerosis and reduced morbidity and mortality rates. Three of these "landmark trials" have examined the long-term effect of statins in patients with previous MI. The Scandinavian Simvastatin Survival Study (4S), the Cholesterol And Recurrent Events (CARE) trial,and the Long Term Intervention with Pravastatin in Ischemic Disease (LIPID) study have shown that a reduction in LDL-C levels of about 25% to 35% leads to a reduction in CAD events of about 24% to 42%. Acute Coronary Syndromes: The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study determine that atorvastatin in patients with unstable angina or non-Q-wave acute MI improves the cardiovascular prognosis by decreasing the combined risk of death (any cause) nonfatal MI, resuscitated cardiac arrest, and worsening angina with new objective evidence of ischemia requiring urgent hospitalization. Non-Lipid-Lowering Uses of Statins

The beneficial effects of statins in ACS may be related to a protective effect on endothelial dysfunction, stabilization of plaque, and modification of the coagulation pathway. Antiproliferative and immunosuppressive actions have been attributed to statins. These effects need to be confirmed in controlled clinical trials and specifically in transplant rejection. Statins also seem to possess a blood pressure lowering effect that may be clinically relevant.The immunosuppressive action of statins includes modulation of T-cell activation, an effect that can provide scientific rationale for using statins as immunosuppressants during organ transplantation.

Conclusions: There is evidence to suggest that statin therapy is associated with a statistically significant reduction in the risk of primary and secondary cardiovascular events. As the confidence intervals for each outcome in each prevention category overlap, it is not possible to differentiate, in terms of relative risk, between the effectiveness of statins in primary and secondary prevention. However, the absolute risk of CHD death/non-fatal MI is higher, and the number needed to treat to avoid such an event is consequently lower, in secondary than in primary prevention.The results of the economic modelling show that statin therapy in secondary prevention is likely to be considered cost-effective. In primary prevention, the cost-effectiveness ratios are dependent on the level of CHD risk and age, but the results for the CVD analyses offer support for the more aggressive treatment recommendation.

REFERENCES http://www.hta.ac.uk/fullmono/mon1114.pdf http://www.medscape.com/viewarticle/408603_2 http://www.medicine.ox.ac.uk/bandolier/booth/cardiac/patcomp.html http://www.medicine.ox.ac.uk/bandolier/booth/cardiac/statecon.html

Pharmacoeconomics of Statin Use Table 1 shows the weighted cost of statins used in the economic modelling. The cost of individual statins is weighted by the trial evidence. The relatively low cost of atorvastatin compared with simvastatin, in Table 2, is due to the high weighting given to the 10-mg cost of atorvastatin (Table 1). Ninety-five per cent of trial patients were in this category, resulting in a large weight being attributed to the low 10-mg cost of 18.03.For simvastatin, all patients were in either the 20- or 40-mg category and 86% were in the more expensive 40-mg category. A higher weight is therefore placed on these costs, resulting in an annual cost for simvastatin of 297 compared with 243 for atorvastatin. The high annual cost of pravastatin is due to 99% of trial patients being in the more expensive 20- or 40-mg categories.The majority of analyses are based on the costs and effectiveness of statins collectively.
TABLE 1 Weighted cost of statins used in analysis Statin Annual cost Atorvastatin 243.10 Fluvastatin 204.00 Pravastatin 387.30 Rosuvastatin 244.10 Simvastatin 296.90 Combined 316.80 Rosuvastatin not included.

TABLE 2 Statin cost and numbers in treatment arm of RCTs 10 mg 20 mg 80 mg Statin Cost No. In Cost No. In Cost No. in (28 tabs) treatment (28 tabs) treatment (28 tabs) treatment arm arm arm

40 mg Cost (28 tabs) No. in treatment arm

Simvastatin 14.01 20.21 1865 23.18 11438 29.03 Atorvastatin 18.03 6981 29.69 29.69 29.69 385 Fluvastatin 12.72 12.72 187 16.00 1518 Pravastatin 16.18 3 29.69 18 29.69 14218 Rosuvastatin 18.03 245 29.69 29.69 4 Combined proprietory and generic cost based on 2004 prices and 2003 prescribing data.

Figures 28 and 29 compare the ICERs estimated for the secondary and primary prevention of CHD events across the age groups. As can be seen, while secondary prevention is more cost-effective than primary prevention across all ages, for patients commencing statin treatment at a young age to prevent the onset of CHD, the costs per QALY are still well within the ranges considered cost-effective.

Threshold analysis A threshold analysis based on risk levels was carried out for primary prevention results.Using a threshold of 30,000 per QALY, the results of the probabilistic analyses for the basecase CHD analyses in secondary prevention demonstrate that statin therapy is cost-effective for all patients with a history of CHD. At the age of 85 years 91% and 84% of secondary prevention ICERs are below 20,000 per QALY for women and men, respectively, while almost all other ICERs across all ages are cost-effective using a threshold of 20,000. Secondary prevention As can be seen from the results presented in the CEACs, there is very little difference in the results for the age bands 45, 55 and 65 years. Primary prevention The 1.5% annual CHD risk level was chosen for illustrative purposes. For patients aged 45 years at 1.5% annual risk of a CHD event, 60% and 92% of ICERs are costeffective using thresholds of 20,000 and 30,000, respectively. However, when examining the costs and benefits associated with cohorts aged 65 years, the proportion of results that are cost-effective reduces to 6% and 9% using the 20,000 threshold, and 55% and 80% using the 30,000 threshold for women and men, respectively