REPORT. on health technology assessment. pursuant to art. 17, para. 7 of Ordinance 9 of of the Ministry of Health of Republic of Bulgaria

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1 REPORT on health technology assessment pursuant to art. 17, para. 7 of Ordinance 9 of of the Ministry of Health of Republic of Bulgaria for medicinal product ATOZET 10 mg/10 mg (film-coated tablets) ATOZET 10 mg/20 mg (film-coated tablets) ATOZET 10 mg/40 mg (film-coated tablets) Adopted on at a session of the Commission on health technologies assessment pursuant to art. 5 of Ordinance 9 of on the conditions and the procedure for health technologies assessment 1

2 I. Analysis of the health problem. 1. The analysis of the health problem includes: 1.1. Description of the health problem based on review of scientific and epidemiological data. Coronary heart disease (CHD), also known as coronary artery disease (CAD) or ischemic heart disease (IHD) is a disease in which a waxy substance called plaque builds up inside the coronary arteries. These arteries supply oxygen-rich blood to your heart. When plaque builds up in the arteries, the condition is called atherosclerosis. Over time, plaque can harden or rupture. Hardened plaque narrows the coronary arteries and reduces the flow of oxygen-rich blood to the heart. If the plaque ruptures, a blood clot can form on its surface. A large blood clot can mostly or completely block blood flow through a coronary artery. If the flow of oxygen-rich blood to your heart muscle is reduced or blocked, angina (stenocardia) or myocardial infarction (heart attack) can occur. Over time, CHD can weaken the heart muscle and lead to heart failure and arrhythmias. CHD includes patients with history of myocardial infarction (MI), unstable and stable stenocardia, procedures on coronary arteries (angioplasty and bypass surgery) or data of clinically significant myocardial ischemia. The risk for CHD equivalents include patients with clinical symptoms of noncoronary forms of atherosclerosis (peripheral arterial disease, aneurism of abdominal aorta and disease of the carotid artery (previous ischemic attacks or stroke of carotid origin or > 50% blocking of the carotid artery), diabetes and 2+ risk factors with 10-year risk of severe CHD > 20%. Coronary heart disease is the first cause of death, years of life lost (YLL) and disability-adjusted life years (DALYs) worldwide. DALYs combine years of life lost, which may be attributed to fatal CHD with years of disability in individuals surviving with chronic stable CHD. In 2013 there were 8.1 million deaths caused by CHD (138 per 100,000 population) and 6.4 million deaths caused by stroke (110 per 100,000), which account respectively for 14.8% and 11.8% of all deaths in the world. Especially in Europe, CHD accounts for almost 1.8 million deaths, 43.6% of all CV deaths or 20% of all deaths in Europe each year. There was increase in the average number of hospitalizations related to CHD in 2012, which was 608 per 100,000 of the population compared to 532 in Age-adjusted CHDrelated mortality rate both for men and women decreased in the last 10 years according to the available data for many of the 53 member states from the European Region of WHO however in few countries it increased over the same period. In the last 5 years there were significant reductions in the annual change of the hospitalization-based mortality rates after acute MI in Europe varying from -1.6% (Israel) to -8.2% (Denmark) due to unspecified reasons. 2

3 For Bulgaria, the data from the European database for mortality rates indicate quite stable mortality rates caused by primary myocardial infarction and ischemic heart disease in the course of time (see Figure 1). Figure 1 Mortality rate due to primary myocardial infarction and ischemic heart disease in Bulgaria In absolute figures, it is reported that annually between 5,000 and 6,000 persons die from primary myocardial infarction and ischemic heart disease (see Figure 2). Figure 2 Annual number of deaths caused by primary myocardial infarction and ischemic heart disease in Bulgaria The estimates show that this is equal to about 5% and 6% of the total number of deaths on national level (see Figure 3). Figure 3 Mortality rate attributed to primary myocardial infarction and ischemic heart disease 3

4 Conclusion: The presented data is sufficient as to volume and content for the incidence of disease of the blood circulation organs in Bulgaria and gives idea about the importance of the health problem dyslipidaemias as they affect a major part of the population. Bulgarian and international databases were used as well as scientific publications about the high share of cardiovascular diseases in morbidity rates and mortality rates in Bulgaria, in Europe and worldwide. The formulations for treatment of dyslipidaemias from the Guidelines of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) are used Description of the proposed health technology. Atozet, MSD is proposed for oral use as film-coated tablets, which contain ezetimibe (10 mg) and atorvastatin calcium tryhidrate (equivalent to 10, 20, 40 or 80 mg), two lipid-lowering agents with supplementary action. Ezetimibe inhibits intestinal absorption of cholesterol. Atorvastatin reduces the plasma concentrations of cholesterol and serum concentrations of lipoproteins by inhibiting the HMG-- CoA reductase. Atozet (ezetimibe/ atorvastatin) is a new fixed-dose combination between arotvastatin and ezetimibe marketed in Europe. Atozet gives important hope to patients who experience unacceptable adverse effects from statin therapy and to those who are not able to achieve adequate LDL-C lowering with statins. FDC like Atozet may improve adherence to therapy compared to the combination of several tablets. For example, patients on combined therapy with one table are 32% more likely to adhere to the therapy compared to patients receiving combination of a few tablets. Adherence to lipid-lowering therapy is connected with improvement of the clinical outcomes, reduced use of healthcare resources and the related expenses. 4

5 1.3. Description of other health technologies that are reimbursed in Bulgaria and that may be used as a therapeutic alternative or as a combined therapy with the proposed health technology. Statin therapy is the most prescribed therapy for cardiovascular prophylaxis. Many large-scale clinical trials have proven that statins considerably reduce cardiovascular morbidity and mortality both in primary and in secondary prophylaxis. It has been also proven that statins slow down the progression and even assist for the regression of coronary atherosclerosis. Ezetemibe may be applied as a second line therapy in combination with statins when the therapeutic goal may not be achieved with the maximum tolerated dose of statins or in patients with intolerance to statins or with counter-indications for these drugs. (The Guidelines of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) for treatment of dyslipidaemias). Medicinal products from the statin group are included in the Positive Drug List for certain indications. 2. Choice of a main comparative therapeutic alternative: 2.1. The main comparative alternative is the one, which most likely will be replaced in the existing medical practice. It includes mainly but not limited to: reimbursed pharmacotherapeutical analogue, which is used for the treatment of the same disease or the first choice therapy Alternative therapies of hypercholesterolemia may include statins, fibrates, niacine, Omega-3 fatty acids and resins. Statins they lower LDL-С but in considerably lower extent and concurrently they are not reimbursed for this indication by the NHIF.. Fibrates increase HDL-C but do not affect LDL-C. Niacine (nicotine acid) slight LDL-C lowering without proven clinical effect on cardiovascular diseases. Not reimbursed by NHIF. Omega-3 fatty acids as a food supplement in addition to the main therapy, they may influence the reduction of cardiovascular diseases. Not reimbursed by NHIF. 5

6 Resins researches demonstrate considerable reductions of CV-related mortality rate but not the general mortality rate. They are not reimbursed by NHIF and are not used in the routine medical practice in Bulgaria. Atozet (ezetimibe/ atorvastatin) is a new fixed-dose combination (FDC) between the widely marketed in Europe atorvastatin and ezetimibe. In the context of the Bulgarian market, this is the first compound containing ezetimibe. Atozet is expected to be used as second line statin monotherapy for high-risk patients who will benefit from additional LDL-C lowering or for patients who do not tolerate high doses statin. Therefore the most appropriate comparator for Atozet is rosuvastatin following insufficient control with first line statin. In some populations high dose of statins may be also considered appropriate The most prescribed reimbursed health technology with the same or equivalent therapeutic indication. The most prescribed reimbursed health technology with the same or equivalent therapeutic indication are statins but therapeutic indications for specific groups of patients are more limited. For this indication there is no other technology reimbursed by NHIF Non-drug therapies and non-treatment when this is most used in the therapeutic practice or when there are no other treatment alternatives; For individuals with low total cardiovascular risk is recommended change in the lifestyle for improvement of the serum lipid profile The choice of the main comparative therapeutic alternative is consistent with the national clinical practice, national consensuses and the pharmacotherapeutic guidelines. The Guidelines of the Task Force of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) for the management of dyslipidaemias are supplementary to the guidelines for CVD prevention in the clinical practice and are intended not only for medical doctors interested in CVD prevention but also for specialists in the clinics for lipid or metabolic diseases who work on dyslipidaemias that are difficult to be classified and treated. They are adopted and are applied in Bulgaria. Table 1 Guidelines for ACS/ CHD lipid targets 6

7 Guidelines for ACS/ CHD lipid targets Guideline/ Year TC LDL-C Non-HDL-C International atherosclerosis society (IAS) 2014 г. Without target <70 mg/dl (1.8 mmol/l) <100 mg/dl (<2.6 mmol/l) European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) Without target <1.8 mmol/l (<70 mg/dl) or 50% from the beginning <2.6 mmol/l (<100 mg/dl) Joint British societies (JBS3) 2014 г. Without target <1.8 mmol/l (<70 mg/dl) <2.5 mmol/l (~<100 mg/dl) The National Institute for Health and Care Excellent (NICE) Clinical guidance 181- Great Britain Without target Indirect target >40% from the beginning American College of Cardiology (ACC)/ American Heart Association (AHA) Without target 50% from the beginning Not target National Lipid Association (NLA)-USA Without target <70 mg/dl (<1.8 mmol/l) <100 mg/dl (<2.6 mmol/l) TC = total cholesterol 3. Perspective of assessment - the perspective is of the paying institution. Analyses from the point of view of the society are used as supplementary. 4. Number of potential patients who will be appropriate for treatment with the new health technology. According to data based on АBC (sensitivity analysis) epidemiological data for the estimated number of the target patients' population for application of the new technology is: Year 1 target population of patients, subject to assumption for 2,2% coverage for the first year, it is expected that 375 patients will be treated. Year patients, with 4,7% coverage 791 patients will be treated Year patients, with 6,8% coverage 1138 patients will be treated 7

8 Based on the performed assessment under Section I. Analysis of the health problem, the Working Commission established that the facts and the described health technology as to volume and content are sufficient for the health technology assessment. II. Comparative analysis of the therapeutic efficacy/ efficiency and safety. ATOZET is a medicinal product for oral use in the form of film-coated tablets containing ezetimibe and atorvastatin, two components that lower the lipid level through complementary mechanisms of action. In all clinical trials in which ezetimibe is applied in combination with statin versus statins, placebo or ezetimibe, the combination significantly and reliably reduces the total-с, LDL-C, Apo B, TG, non-hdl- C and significantly increases the good HDL-C versus the two molecules on their own, which shows their synergism. This result is due to the mechanism of action of the two molecules included in the fixed combination, the information for which is widely discussed and described in a number of scientific articles as well as in the SPC of the medicinal product. Plasma cholesterol in human body is derived in two ways - by intestinal absorption (from food) and endogenous synthesis. Ezetimibe inhibits the intestinal absorption of cholesterol while atorvastatin inhibits its synthesis in the body thus the two components lower the cholesterol level in synergistic manner. The combination of the two components significantly reduces the liver cholesterol, has increased expression of LDL receptors and respectively increased LDL-C clearance. The results from the additional trials carried out by Kater A-L et al. (2010) show that the synergistic effect of ezetimibe and statin significantly and statistically significant influences the cholesterol lowering and the inflammatory status in patients based on С- reactive protein (CRT) and interleucin ( IL-2). All clinical trials presented in the analysis assessing ezetimibe + atorvastatin use LDL-C reduction in per cent from the baseline until the final assessment as a main efficacy measure. LDL-C reduction is of important clinical significance. For example for patients with ACS and CHD at high to very high risk for future cardiovascular experiences. For all patients with high LDL-C it is of great importance that the target levels are <70 mg/dl because the lowering of levels results in considerably less cardiovascular experiences mainly due to the lowering of the number of important clinically significant end results as myocardial infarction and ischemic insult. Although interim, this end point is an important measure considering the strong and convincing evidence published in numerous national and international magazines 8

9 Concerning the connection between LDL-C reduction and the prevention of experiences related to cardiovascular diseases (CVD) including death, proven in a number of trials, some of which are presented in the analysis. For example, in meta-analysis of 62 trials involving 216,616 patients, each LDL-C reduction by 1.0 mmol/l accounts for 15.6% reduction of mortality rate by any causes, 28.0% reduction of CHD-related mortality rate and 26.6% reduction of each CHD experience. (Gould) Another meta-analysis of 170,255 patients from 76 randomized trials presented in the analysis, statin therapy reduces mortality in general by 10%, mortality related to cardiovascular disease by 20%, from fatal myocardial infarction by 18%, from non-fatal MI by 26%, from revascularization by 5% and combination of fatal and non-fatal stroke by 14%. (Mills) Data from the recently published research IMPROVE-IT (52), which proves that ezetimibe is the first non-statin drug, which in combination with statin significantly reduces the CVD-related mortality rate, the myocardial infarction or insult by 10%, the ischemic insult by 21% and the myocardial infarction by 13% versus statin monotherapy. Convincing evidence about the relation between LDL-C lowering and considerably less cardiovascular experiences has been reflected in the recommendations of a number of cardiological societies such as the European ESC/ EAS, for example. In the guidelines for treatment of dyslipidaemias they recommend as a main goal the LDL-C lowering, recommendations supported by the Bulgarian Society of Cardiologists. The analysis reviewed all six clinical trials, which assess safety and efficacy of the combination ezetimibe and atorvastatin in patients with hypercholesterolemia who are exposed to moderate or high risk of CHD. There is no clinical trial with fixed combination of ezetimibe/ atorvastatin both presented in the analysis of the company and available in literature and the electronic databases. All available data are from trials in which ezetimibe is added to atorvastatin in the required for the purpose of the trial milligrams. Results from trial cover sufficiently long period of follow-up (Ballantyne), which shows the long-term safety and tolerance of ezetimibe + atorvastatin. As it was discussed above, LDL-C lowering is of main importance as it results in considerable reduction of the general risk of CVD- related experiences including death. A few big meta analyses presented in the analysis of Atozet show the relation between LDL-C and summary of risk of CV experiences. Table 1. Relation between LDL-C and summary of the risk of CV experiences from major meta analyses Relation between LDL-C and summary of the risk of CV experiences from major meta analyses Author of the research Analysed researches LDL-C lowering Reduction of the relative risk for CV event Law 85 placebo controlled trials 1.0 mmol/l IHD death/ non-fatal MI of LDL-C reduction... (39 mg/dl) Experiences by trial year: by any method: 52% of participants 1. 11% (95% CI, 4-18%) 9

10 had known vascular disease 2.24%(17-30%) CV disease upon enrolment %(28-37%) 6+.36%(26-45%) Gould 64 controlled trials (42 secondary; 13 primary prophylaxis 1.0 mmol/l (39 mg/dl) Death by any cause: 15.6% CHD deaths: 28.0 Each CHD event: 26.6% Mills 76 randomized trials of statins 10% Absolute reduction Death by any cause: 1.1% (95% CI, ) CTTC 27 trials of statins (22 statin versus control, 5 versus less statin) with individuals at low risk of vascular experiences 1.0 mmol/l (39 mg/dl) Large vascular experiences: 79% (RR 95% CI, ) Vascular death: 12% (RR 95% CI, ) IHD = ischemic heart disease, CI = certainty interval, RR = relative risk, CTTC = Cholesterol treatment trials collaborators In early meta-analysis of 58 placebo controlled trials of cholesterol reduction by any means and IHD experiences, LDL-C reduction by 1.0 mmol/l (39 mg/dl) reduces the risk of IHD by 11% during the first year, by 24% during the second year, by 33% from the third to fifth year and by 36% thereafter. Statins lower LDL-C by 1.8 mmol/l on average, which reduces the risk of IHD experiences by 60%.(74) Hypercholesterolemia is an important risk factor for CVD and the efficient treatment considerably reduces the cardiovascular risk. In meta-analysis of 14 randomized trials of statins, total cholesterol (TC) reduction by 10% is connected with 25% reduction in incidence of coronary arterial disease for five years and LDL-C reduction by 40 mg/dl (1 mmol/l) with statin therapy results in reduction of the risk for coronary experiences by 23%. This proportional reduction in its major part is independent on the LDL-C levels before commencement of statin therapy. (77) All that once more proves the role of the LDL-C reduction and the clinical significance of the achievement of the target levels shown in the guidelines for treatment of dyslipidaemias. Thus although being an interim clinical result, LDL-C lowering results in clinically significant long-term results. Hypercholesterolemia is a condition, which includes the availability of increased concentrations of lipids in the cells and the plasma of the circulating blood. Anomalies in lipid metabolism may occur for several reasons, including defects in receptors, enzymes and apolipoprotein. These anomalies may result in increased levels of LDL-C and/ or triglycerides or low levels of HDL-C. The high level LDL-C is clinically significant because it is connected with two serious diseases: atherosclerosis and consequently CHD. The main diseases that are influenced by Atozet therapy are those connected with cardiovascular diseases (CVD), which refer to the group of heart disorders and blood vessels and include: coronary heart disease (CHD, which is the most frequent), acute coronary syndrome (ACS) including unstable angina (UA), Non ST-segment elevation myocardial infarction (NSTEMI), ST-segment elevation myocardial infarction 10

11 (STEMI), cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, inborn cardiac disease, deep venous thrombosis and lung embolism. Risk for cardiovascular experience upon ACS/CHD Individuals in the acute phase of MI are at risk of disease and death, which is between 1.5 и 15 times higher compared to the general population. Within one year after the first MI, 19% of men and 26% of women at the age 45 will die and this rate will increase respectively to 36% and 47% within 5 years after the first MI. 15% of men and 22% of women with first MI at the age of will experience recurrent MI or fatal CHD within 5 years. Coronary heart disease is the first cause of death, years of life lost (YLL) and disability-adjusted life years (DALYs) worldwide. Data from the European database for Bulgaria indicate comparatively stable mortality rates related to primary myocardial infarction and ischemic heart disease in the course of time and annually between 5,000 and 6,000 individuals die from primary myocardial infarction and ischemic heart disease respectively, which is about 5%-6% from the total mortality rate in Bulgaria. In Bulgaria Nikos et al. report CHD-related costs on the basis of data from Eurostat. The common healthcare expenses, including outpatient treatment, inpatient treatment and expenses for drugs are estimated to 56,279,000. This represents almost 2% of the total healthcare budget in Expenses not related to healthcare, including production losses and overall care, are estimated to almost 80 million. Although the economic burden of ACS and CHD in Bulgaria is not duly documented, information about patients discharged from hospital due to diseases of cardiovascular system in Europe show that the rates are the second highest. As it was shown above on the basis of data from the provided meta-analyses, it is also concluded that there is relation between the LDL-C reduction and the prevention cardiovascular diseases related experiences, including death. On the basis of all data provided in the analysis, it may be reasonably concluded that the use of interim end result such as LDL-C lowering is justified and that it is closely related to long-term results, which have important economic significance. In the six clinical trials provided in the analysis of Atozet, the comparison is made to placebo (2 trials) and to the currently reimbursed atorvastatin (4 trials) and rosuvastatin (1 trial). All six clinical trials available at present concerning the combination ezetimibe and atorvastatin are presented in the analysis for Atozet. All six clinical trials were performed by MSD/ Merck & Co. and for this reason as it was described in the analysis, there was no need of systematic search of trials connected with this medicinal product because all data from the trials conducted by the sponsor are internally available. 11

12 Thorough systematic review is made only concerning the comparative medicinal products in the analysis (Mills 2011 г.) concerning secondary prevention of CV experiences/ death. Data from the six clinical trials reviewed in this analysis: Ballantyne CM, Houri J, Notarbartolo A, et al., Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia. Circulation 2003;107: In double-blind randomized trial were compared ten different regimes of monotherapy with ezetimibe (10 mg), monotherapy with atorvastatin (10, 20, 40, 80 mg), ezetimibe plus atorvastatin (10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg, 10 mg/80 mg) or placebo in 628 patients with primary hypercholesterolemia. Following 12 weeks treatment, summarized analyses show that coadministration of ezetimibe and atorvastatin results in mean change in LDL-cholesterol compared to the baseline by 54,5% versus 42,5% for atorvastatin monotherapy (p<0,01). Coadministration results in significantly greater LDL-C reduction versus ezetimibe monotherapy ( 18.4%; p<0.01). Baseline LDL C is above the target level ATP III and below the target level upon final assessment in 85% of patients receiving combined therapy versus 73% of patients receiving atorvastatin monotherapy (P<0.01). Ballantyne CM, Lipka LJ, Sager PT, et al. Long-term safety and tolerability profile of ezetimibe and atorvastatin coadministration therapy in patients with primary hypercholesterolemia. Int J Clin Pract. 2004;58: Upon completion of a 12 week randomised, double-blind, placebo-controlled study comparing ezetimibe 10 mg; atorvastatin 10, 20, 40 or 80 mg; ezetimibe plus atorvastatin 10, 20, 40 or 80 mg or placebo, 246 patients were enrolled in a 12-month extension. Patients are randomized to receive 10 mg ezetimibe or placebo (double blind) coadministered with atorvastatin 10 mg (open-label). Upon completion of the extended trial, coadministration of ezetimibe and atorvastatin results in greater LDL-cholesterol reduction versus atorvastatin monotherapy ( 48.4% versus 38.6%; p<0.01). Coadministration also results in considerably greater reduction of the total cholesterol and triglycerides compared to atorvastatin monotherapy. Higher percentage of patients achieve the target level for NCEP ATIP II LDL-C upon coadministration of ezetimibe and atorvastatin (91%) versus atorvastatin monotherapy (78%) (p = 0.02). Conard SE, Bays HE, Leiter LA, et al. Efficacy and safety of ezetimibe added on to atorvastatin (20 mg) versus uptitration of atorvastatin (to 40 mg) in hypercholesteraemic patients at moderately high risk for coronary heart disease (TEMPO) Am J Cardiol. 2008;102: The TEMPO trial randomized 196 patients at moderately high risk for CHD (but without diabetes mellitus or medical history of previously diagnosed cardiovascular disease) who fail to reach the target level for LDL-C <100 mg/dl with atorvastatin 20 mg, to receive ezetimibe 10 mg plus atorvastatin 20 mg or double dose atorvastatin monotherapy 40 mg for 6 weeks. Upon completion of this trial for primary prevention, considerably greater reduction of LDL-cholesterol compared to the baseline is established upon combined therapy versus higher dose atorvastatin (respectively 31% versus 11%; p<0.001). 12

13 Combined therapy is also connected with greater percentage of patients who reach the target level for LDL-C <100 mg/dl in 6 weeks versus atorvastatin 40 mg (respectively 84% versus 49%; p<0.001). Rate of clinical and laboratory adverse experiences is generally similar between the groups. Three randomized control tests show that the coadministration of ezetimibe and atorvastatin is efficient for LDL-cholesterol lowering at patients at high risk of CHD. Stein E, Stender S, Mata P, et al., Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin. Am Heart J 2004;148(3): This was a 14-week randomized, double-blind, active-controlled study conducted with 621 patients at high risk of CHD who receive atorvastatin 10 mg upon the randomization. The trial compared ezetimibe 10 mg plus response-based atorvastatin dose titration individually to achieve the target levels for LDL-C in subjects at high risk of CHD who fail to achieve the target levels of LDL-C with the starting dose of atorvastatin. Patients were randomized to receive additional blind therapy with ezetimibe 10 mg or atorvastatin 10 mg. For patients who failed to achieve the LDL-C target 100 mg/dl in week 4, the atorvastatin dose was doubled. This was repeated in week 9 for those who still failed to achieve the LDL- C target. Approximately 3 times more patients achieved the LDL-C target 100 mg/dl in week fourteen with combination regime versus atorvastatin monotherapy (respectively 22% versus 7%; p<0.01). This is not dependent on the higher doses to the maximum doses atorvastatin in the group receiving atorvastatin. The mean change of LDL-C from the baseline is 33.2% for the combined regime group versus 20.3% for the atorvastatin group. The safety and tolerability profile of the combined regime is similar to the profile for atorvastatin monotherapy. Leiter LA, Bays H, Conard S, et al., Efficacy and safety of ezetimibe added on to atorvastatin (40 mg) compared with uptitration of atorvastatin (to 80 mg) in hypercholesteraemic patients at high risk of coronary heart disease. (EZ-PATH) Am J Cardiol 2008;102: The EZ-PATH trial was conducted to assess efficacy of ezetimibe added on to atorvastatin 40 mg/day compared with uptitration of atorvastatin to 80 mg/day in hypercholesteraemic patients at high risk of coronary heart disease with LDL cholesterol 70 mg/dl. In this trial 579 patients at high risk of CHD were randomly assigned to receive ezetimibe 10 mg plus atorvastatin 40 mg/day or were randomly assigned to receive atorvastatin 80 mg as a monotherapy for 6 weeks. Ezetimibe plus atorvastatin is connected with greater reduction of LDL C compared with the baseline following 6 weeks versus atorvastatin 80 mg (respectively 27% versus 11%, ; p<0.001). Additionally greater number of patients treated with atorvastatin 40 mg plus ezetimibe achieve LDL-C <70 mg/dl versus patients treated with atorvastatin 80 mg (74% versus 32%, 13

14 p<0.001). Safety and tolerability profiles and incidence of liver and muscle adverse experiences were generally similar between groups. Bays HE, Averna M, Majul C, et al., Efficacy and safety of ezetimibe added to atorvastatin versus atorvastatin uptitration or switching to rosuvastatin in patients with primary hypercholesterolemia. (PACE) Am J Cardiol 2013;112(12): PACE trial compares the efficacy for LDL-C reduction of ezetimibe added to atorvastatin 10 or 20 mg versus doubling atorvastatin or switching to (or doubling) rosuvastatin. It randomizes 1,547 patients at high risk of atherosclerotic cardiovascular disease with LDL-C > 100 mg/dl and < 160 mg/dl who receive atorvastatin 10 mg/day. In Period I patients are assigned to 3 different groups to compare efficacy/ safety of: 1) adding ezetimibe 10 mg to stable atorvastatin 10 mg, 2) doubling atorvastatin to 20 mg, or 3) switching to rosuvastatin 10 mg. Subjects who persisted with elevated LDL-C levels ( 100 and 160 mg/dl) after period I, entered period II. In the last period, subjects on atorvastatin 20 mg had ezetimibe added to their atorvastatin 20 mg, or uptitrated their atorvastatin to 40 mg; subjects on rosuvastatin 10 mg switched to atorvastatin 20 mg plus ezetimibe or uptitrated their rosuvastatin to 20 mg. At the end of period I, ezetimibe plus atorvastatin 10 mg reduced LDL-C significantly more than atorvastatin 20 mg or rosuvastatin 10 mg (22.2% vs 9.5% or 13.0%, respectively, p <0.001). At the end of period II, ezetimibe plus atorvastatin 20 mg reduced LDL-C significantly more than atorvastatin 40 mg (17.4% vs 6.9%, p <0.001); switching from rosuvastatin 10 mg to ezetimibe plus atorvastatin 20 mg reduced LDL-C significantly more than uptitrating to rosuvastatin 20 mg (17.1% vs 7.5%, p <0.001). Relative to comparative treatments, ezetimibe added to atorvastatin 10 mg (period I) or atorvastatin 20 mg (period II) produced significantly greater percent attainment of LDL-C targets <100 or <70 mg/dl. Reports of adverse experiences were generally similar among groups. Criteria for the selection of the subjects in the six clinical trials are described in details and basically these are adults with hypercholesterolemia, different accompanying diseases and risk of cardiovascular experiences. The basic characteristics of the patients from the 6 clinical trials are presented below: Table 13 Baseline characteristics of patients enrolled for the Ballantyne et al. trial Baseline characteristics for the Hypercholesterolemia Trial Placebo (n=60) Ezetimibe 10 mg (n=65) All atorvastatin (n=248) Mean age (years) All ezetimibe + atorvastatin Men, n (%) 29 (48) 29 (45) 95 (38) 107 (42) 14

15 White, n (%) 49 (82) 57 (88) 205 (83) 222 (87) History of CHD, n (%) 21 (35) 31 (48) 104 (42) 101 (40) History of CHD, n (%) 5 (8) 6 (9) 23 (9) 23 (9) Direct LDL-C, mean, mmol/l Estimated LDL-C, mean, mmol/l Total cholesterol, (mean), mmol/l Triglycerides, mmol/l mean, HDL-C, mean, mmol/l hs-crp, mean, mg/l Table 14 Baseline characteristics of patients enrolled for the Ballantyne et al. trial 2004 Baseline characteristics for the extension of the Ballantyne trial Characteristics Atorvastatin (n=45) Ezetimibe + Atorvastatin 10 mg (n=201) Age, mean (range), years 58.5 (34 76) 57.6 (26 86) Men, n (%) 23 (51) 78 (39) Caucasian, n (%) 39 (87) 174 (87) Hereditary burden for CHD, n (%) 22 (49) 85 (42) LDL-C, mean,mmol/l HDL-C, mean, mmol/l Triglycerides, mean, mmol/l Total cholesterol, mean, mmol/l Table 15 Baseline characteristics of patients enrolled for the TEMPO trial Baseline characteristics in TEMPO Characteristics Ezetimibe Atorvastatin (n=98) 20 + mg Age, years, mean Men, n (%) 58 (59%) 49 (50%) White, n (%) 58 (59%) 60 (61%) 2 CHD risk factors (10-annual risk for CHD=10% 20%),n(%) 94 (96%) 96 (98%) Atorvastatin 40 mg (n=98) 15

16 Table 16 Baseline characteristics of patients enrolled for the Stein et al. trial. Baseline characteristics for the Stein trial Nd,duje,rijrud Ezetimibe + Atorvastatin (n=305) Atorvastatin monotherapy (n=316) Age, mean (interim) г (54) 51.6 (53) Men, n (%) 159 (52) 171 (54) White, n (%) 279 (91) 289 (91) History of CHD, n (%) 90 (30) 100 (32) Direct LDL-C, mean, mg/dl Estimated LDL-C, mean, mg/dl Total cholesterol, (mean), mg/dl Triglycerides, mean, mg/dl HDL-C, mean, mg/dl Non-HDL-C, mean, mg/dl Table 17 Baseline characteristics of patients enrolled for the EZ-PATH trial. Baseline characteristics in EZ-PATH Characteristics Ezetimibe Atorvastatin (n=288) 40 + mg Atorvastatin 80 mg (n=291) Age, years, mean (SD) 61 (10) 62 (9) Men, n (%) 173 (60%) 178 (61%) White, n (%) 237 (82%) 232 (80%) 2 CHD risk factors (10-annual CHD risk >20%), n (%) 93 (32%) 114/290 (39%) LDL-C, mean, mg/dl HDL-C, mean, mg/dl Total cholesterol, (mean), mg/dl Triglycerides, mean, mg/dl Non-HDL-C, mean, mg/dl Apo B, mean, mg/dl apoa-i, mean, mg/dl hscrp, mean, mg/l

17 Table 18 Baseline characteristics of patients enrolled for the PACE trial. Baseline characteristics in PACE Period I E10 + E10 + A10 - A10 A20 R10 -> E10 +A10 A20 -- > E10 +A20 Period II A20 -- > A40 R10 -- > E10 +A20 R10 -- > R20 N Men (40.8%) (47.6%) (48.2%) 14 (50%) (55.6%) (50%) (47.4%) (51.9%) Age (9.4) (10.2) (9.7) 61.9 (8.7) 59.6 (10.9) (10.9) 59.1 (10.2) (10.1) White (94.2%) (96.3%) (95%) 26 (92.9%) (96.8%) (96.8%) (94.9%) (95.1%) CVD (50.8%) (49.3%) (50.7%) 13 (46.4%) (50.8%) (44.4%) (50.4%) (49%) Diabetes (50%) (46%) (47.8%) 11 (39.3%) (44.4%) (45.2%) (49.6%) (44.7%) LDL-C (37) 119 (16) (21) 119 (16) (18) (17) (18) (17) Total Cholesterol (46) 202 (23) (25) 204 (24) (25) (23) (24) (23) Triglycerides 127 (80) 148 (75) 147 (73) 139 (105) 144 (79) (65) 150 (61) (73) HDL-C 53 (13) 53 (12) 53 (13) 53 (15) 51 (12) 52 (13) 53 (15) 54 (13) The main initial characteristics of patients enrolled in the six clinical trials include: mean age between 51 and 61 years, with approximate ratio between men and women, with prevailing population (from 80% to 90%) from the Caucasian (white) race, between 30% to 50% with history of CHD at high to very high risk of cardiovascular experiences and high LDL-C levels (2.6 to 4.8 mmol/l). All trials are double blind randomized with different duration. Primary end point is the percentage reduction of direct LDL-C. The secondary end point in various trials include these or combinations of TC, TG, HDL-C, HDL2-C, HDL3-C, non HDL-C, lipoprotein(s), apoa-i, apob, and total cholesterol: HDL-C and direct LDL-C: HDL-C ratio, etc. Patients The patients development by trials is as follows: Ballantyne et al

18 Due to the lack of specific diagram, the patients distribution in the trial is described below: 1703 were screened for this trial and 628 of the met the criteria for enrolment and were assigned randomly to each arm placebo (n=60), ezetimibe (10 mg) (n=65); atorvastatin (n=248) and ezetimibe + atorvastatin (n=255). The trial was interrupted earlier for 52 (8%) patients due to adverse reactions (34 patients), at the request of the patients (10 patients), non-adherence to the protocol (5 patients) and loss for follow-up (3 patients). There was no trend in the therapeutic groups in the assignment of patients who terminated the therapy or in the reasons for termination. Ballantyne et al Subject to lack of specific diagram, below is described the allocation of patients in the trial: 576 patients completed the 12-week basic trial (Ballantyne et al (73)) and 246 of them were assigned randomly to 12-month extension trial atorvastatin (n=45) and ezetimibe + atorvastatin (n=201). From the individuals assigned randomly to EZE1ATV (n5201) and ATV monotherapy (n=545) groups, respectively 83 and 87% of the subjects completed the 12-month period of extension. The percentage of patients who terminated the therapy due to adverse reactions was similar between the groups with EZE1ATV (9%) and ATV monotherapy (7%). Termination by patients' request, nonadherence to the protocol and loss for follow-up was not different between the therapeutic groups (data are not shown). Conard et al (TEMPO trial) Allocation of patients in the TEMPO trial is presented on the figure below. Ballantyne et al Allocation of patients in the Stein et al. trial is presented on the figure below. 18

19 Leiter et al (EZ-PATH trial) The allocation of patients in the EZ-PATH trial is presented on the figure below. Bays et al (PACE trial) Grouping of patients in the PACE trial is presented below. 19

20 Information concerning the patients who terminated participation in the clinical trials: In the trial Ballantyne et al were randomized 628 patients and 52 (8%) of them terminate participation. In Ballantyne et al. 2004, 576 patients completed the 12-week basic trial (Ballantyne et al. 2003) and 246 of them were randomized in the 12-month trial. The percentage of patients who terminated the therapy due to adverse reactions was similar between the groups with ezetimibe + atorvastatin (9%) and atorvastatin monotherapy (7%). Conard et al (TEMPO trial), 196 patients were randomized and 183 of them completed the 6- week trial. Stein et al. 2004, 621 were randomly assigned to the two arms and similar number - 26 and 27 respectively terminated their participation, and 568 patients completed the trial successfully. 20

21 Leiter et al (EZ-PATH trial), 579 patients were randomized and 22 of them withdrew from the trial. Bays et al (PACE trial), 1547 patients were randomized and in the first phase 87 patients dropped off and in the second phase 29 patients dropped off. On the basis of the complete data from the six clinical trials withdrawal of patients is due to four main reasons: due to adverse reactions in about 30% of patients, at the patients' request in 40% of the cases, non-adherence to the protocol - about 10% and due to loss for follow-up - about 20%. The overall assessment of the quality of included trials shows that the combination of ezetimibe + atorvastatin is thoroughly studied and is a proven efficient and safe choice for treatment of patients with hypercholesterolemia. All clinical trials are well modelled and feature the highest quality, and they prove convincingly that the treatment with the combination ezetimibe/ atorvastatin is efficient and safe. Find below the results from all 6 clinical trials, which show the superiority of the combination ezetimibe + atorvastatin versus placebo or active controls such as atorvastatin, ezetimibe or rosuvastatine in different concentrations. Ballantyne et al The coadministration of ezetimibe + atorvastatin results in greater mean reduction of direct LDL-C from the baseline versus atorvastatin alone or ezetimibe alone (ezetimibe + atorvastatin resulted in 54.5% LDL-C reduction versus 42.4% reduction with atorvastatin monotherapy (p<0.001)). Coadministration of ezetimibe + atorvastatin is well tolerated. Safety measurements (laboratory tests, vital signs, electrocardiograms and cardiac and lung examinations) didn't show clinically significant differences between the safety profiles of the groups with coadministration and atorvastatin monotherapy. Ballantyne et al Coadministration of ezetimibe + atorvastatin was connected with significantly (p<0.01) higher % reductions from the baseline to the end point of the extension in LDL-C and triglycerides versus atorvastatin monotherapy. Treatment with ezetimibe + atorvastatin is well-tolerated. Therapeutic groups assigned to ezetimibe + atorvastatin and atorvastatin were similar as to incidence of therapyrelated adverse reactions (respectively 22% versus 27%), termination of therapy due to therapy-related adverse reactions (respectively 6% versus 7%) and serious adverse reactions (8% versus 11 %). 21

22 Conard et al (TEMPO trial) In Conard et al (TEMPO trial), the coadministration of ezetimibe 10 mg + atorvastatin 20 mg was related to greater reduction of LDL-C following 6 weeks versus atorvastatin 40 mg (respectively 31% versus 11%; p<0.001). Greater reduction of LDL-C among all predefined subgroups including age, gender, race, region, body mass index, metabolic syndrome, baseline LDL-C, baseline HDL-C and baseline triglyceride with value of reduction LDL-C similar to 22

23 that of the whole group. Both ezetimibe 10 mg + atorvastatin 20 mg and atorvastatin 40 were generally safe and well-tolerated with similar incidences of clinical and laboratory adverse experiences. Ballantyne et al Significantly greater number of patients in the group ezetimibe + atorvastatin versus the group assigned to atorvastatin achieved LDL-C 100 mg/dl in 14 weeks (22% versus 7%, p<0.01) This effect is independent of gender, race, body mass index and Non-FH diagnosis, hypertension and diabetes mellitus. Incidence of adverse experiences was similar between the therapeutic groups: the group assigned to ezetimibe + atorvastatin (63%), the group assigned to atorvastatin (58%). Adverse experiences were similar between the therapeutic groups (4% for each group). Leiter et al (EZ-PATH trial) The primary end point was related to greater reduction of LDL-C following 6 weeks therapy with ezetimibe 10 mg + atorvastatin 40 mg versus atorvastatin 80 mg (respectively 27% versus 11%; p<0.001). Greater percentage of patients achieving LDL-C <70 mg/dl following 6 weeks versus atorvastatin 80 mg (respectively 74% versus 32%; p<0.001). Compared to atorvastatin 80 mg, reduction of non-hdl-c, total cholesterol, apob and triglycerides (p<0.001 for all comparisons). Considerable differences (p<0.001) were observed also in the lipid rations, including total/ HDL cholesterol, LDL/HDL cholesterol, apob/apoa-i and non-hdl/hdl cholesterol ratios. Both ezetimibe 10 mg + atorvastatin 40 mg and atorvastatin 80 were generally safe and well-tolerated with similar incidences of clinical and laboratory adverse experiences. The investigators didn't consider that any of the serious adverse experiences were connected with the trial. 23

24 Bays et al (PACE trial) 24

25 For patients with LDL-C > 100 and < 160 mg/dl after initial therapy with atorvastatin 10 mg, adding ezetimibe to atorvastatin 10 mg caused greater reduction of LDL-C versus uptitration of atorvastatin to 20 mg or switching to 10 mg. Switching from rosuvastatin 10 mg to ezetimibe plus atorvastatin 20 mg caused greater reductions in LDL-C and achievement of LDL-C <100 or <70 mg/dl versus uptitration of rosuvastatin to 20 mg. Adding ezetimibe to atorvastatin 20 mg also caused greater reduction to general cholesterol, non- HDL-C and all measured lipid and lipoprotein ratios versus atorvastatin 40 mg or rosuvastatin 20 mg. Ezetimibe plus atorvastatin (10 mg or 20 mg), atorvastatin monotherapy (10 mg, 20 mg or 40 mg), and rosuvastatin monotherapy (10 mg or 20 mg) were generally well tolerated during this 18-week trial. The data from the clinical trials presented above may lead to the conclusion that the combination ezetimibe/ atorvastatin is applicable to patients routinely treated in Bulgaria. Similarities as to ethnicity and demographic characteristics between the populations included in the clinical trials assessing ezetimibe and atorvastatin and those patients observed in the clinical practice in Bulgaria suggest that to a great extent the results are really valid for Bulgaria. As evident from the above results from the 6 randomized clinical trials it may be definitively concluded that the combination ezetimibe + atorvastatin is proven to be statistically significant related to greater mean reduction of LDL-C as well as the other indicators versus placebo, atorvastatin, ezetimibe or rosuvastatin in different concentrations. In conclusion from the presented data from randomized clinical trials for ezetimibe + atorvastatin it may be concluded that: Atozet fixed combination ezetimibe + atorvastatin is very well studied and proven as efficient and safe option for treatment of hypercholesteraemic patients. All six trial are well modelled and of highest quality ensuring convincing evidence for the role of Atozet for the therapy of hypercholesteraemic patients. This combination is substantially better than placebo, atorvastatin or rosuvastatin upon LDL-C reduction. The greater LDL-C reduction is expected to reduce the cardiovascular experiences and death, which on its part is expected to reduce the expenses of the healthcare system connected with emergency hospitalization and therapy, further drug therapy, additional hospitalizations and tests related to complications. Efficacy of ezetimibe + atorvastatin is permanent for all patients regardless of the baseline levels of LDL-C, which suggests that similar efficacy may be observed for the patients in the clinical practice in Bulgaria. The analysis of safety and tolerability data from the presented trials shows that the combination of ezetimibe + atorvastatin has favourable safety and tolerability profile. Adverse experiences are generally balanced between the groups in the individual 25

26 trials and they are mild to moderate. The most common adverse experiences are two - diarrhoea and myalgia. Myalgia is clinically significant and it is proven to be temporarily connected with statin administration. It should be noted that the lowest fixed combination ezetimibe + atorvastatin 10mg/10 mg is comparable as to efficacy to the highest dose of atorvastatin 80 mg however avoiding the dosedependent adverse effects of the statin therapy (Ballantyne et al. 2003). Alternative therapies of hypercholesterolemia may include statins, fibrates, niacin, Omega3 fatty acids and resins. Statins they lower LDL-С but to a considerably lower extent and concurrently they are not reimbursed for this indication by the NHIF.. Fibrates increase HDL-C but do not affect LDL-C. Niacin (nicotine acid) slight LDL-C lowering without proven clinical effect on cardiovascular diseases. Not reimbursed by NHIF. Omega-3 fatty acids as a food supplement in addition to the main therapy, they may influence the reduction of cardiovascular diseases. Not reimbursed by NHIF. Resins researches demonstrate considerable reductions of CV-related mortality rate but not the general mortality rate. They are not reimbursed by NHIF and are not used in the routine medical practice in Bulgaria. At present other health technology for treatment of hypercholesterolemia, reimbursed by NHIF, is not available. Based on the thorough analysis of efficacy, efficiency and safety of Atozet, it may be concluded that the combined therapy ezetimibe + atorvastatin is innovative fixed combined therapy, which results in efficient greater LDL-C reduction versus statins alone and with safety profile comparable to the one of the statins alone. Atozet provides a new option, which may satisfy the unmet needs of the hypercholesteraemic patients, which are not adequately controlled and patients with ischemic heart disease and history of acute coronary syndrome for prevention of cardiovascular experiences. The expected use of Atozet may be as a second line medicinal product following statin monotherapy for patients at moderate to high risk, who will benefit from additional LDL-C reduction and patients with intolerance to statins. 26

27 III. Analysis of pharmacoeconomic indicators. 1. Pharmacoeconomic analysis includes systematic review of published economic analyses consistent with the target population of patients and used some of the following analytical techniques: 1.1. cost - efficacy analysis; Analysis was made of the results of other trials assessing efficacy from adding Ezetimibe to the therapy of patients versus the use of statin-based drugs only. On the basis of these results and data about mortality by other causes based on the Bulgarian mortality tables (biometric tables) a model has been prepared, individually for the male and female population, because the risk for cardiovascular event (CVE) is different between genders. A model has been developed for economic assessment of Atozet, which uses as a measurer of efficiency the risk of occurrence of coronary heart disease, cardiovascular disease and insult for each possible therapy through risk equations. Reduction of incidence is a function of the baseline LDL-C of a patient and the applied therapy. Table Efficacy parameters used in the model Group of parameters Parameter Base Min Max LDL efficacy Statin Adding EZ Incidence reduction Fatal CHD Non-fatal CHDI Fatal stroke Non-fatal stroke Information about the clinical benefits of Atozet concerning other health measurers is presented in the previous section, which a description is made of the disease for which the health technology is intended, including short-term and long-term consequences and the severity of the disease. As a result of the application of the new technology two more indicators were derived - slight increase of survival rate and slight increase of QALYs cost - benefit analysis; Accumulated costs from the introduction of the new drug technology and benefits (QALY), individually for the male and female population are presented in the form of a table (see the tables below) based on the results of the basic model. 27

28 Table. Base case: 60-year old male patients with CHD, diabetes and baseline LDL-C=3.0 mmol/l Parameter Switching to rosuvastatin 10mg Switching to EZ/AT 10/20 mg EZ - Rosuva RX costs , , Costs per experience 15, , Total costs 15, , , Years of life QALYs Table. Base case: 60-year old female patients with CHD, diabetes and baseline LDL-C=3.0 mmol/l Parameter Switching to rosuvastatin 10mg Switching to EZ/AT 10/20 mg EZ - Rosuva RX costs , , Costs per experience 17, , Total costs 17, , , Years of life QALYs According to the calculations from the model, women have higher costs but also greater benefits with the alternative therapies compared to men. In both cases patients treated with Atozet live longer and accumulate more QALYs versus patients receiving rosuvastatin 10 mg. For women over the age of 60, Atozet increases the years of life and QALYs respectively by 0.16 and 0.15 years versus uptitration of rosuvastatin. The total costs for switching to Atozet for women are BGN 5, more versus switching to rosuvastatin 10 mg. The same results are observed for men over the age of 60 and the benefits from switching to Atozet are 0.17 and 0.16 years respectively for measurers for improvement of the years of life and QALYs. The total costs for switching to Atozet for women are BGN 5, more versus switching to rosuvastatin 10 mg. 28

29 1.3. cost - benefit analysis; Based on EUROASPIRE III trial were analysed all costs related to the application of the new technology and the benefits thereof and it is noted that all variables are adapted to the conditions in Bulgaria. It also includes the prices of all clinical pathways from 2010, which are significant for the analysis and are adjusted with the inflation rate as at 2016 (according to data of NSI). Optimization of prophylaxis includes that smoking is stopped and taking into account expenses for 12-week drug therapy added by the expenses for two visits to cardiologist and three subsequent visits to support the patient's efforts. The estimates include also expenses for drugs and visits to cardiologist for two years, which contribute to cholesterol lowering and blood pressure normalization. Efficient prophylaxis should result in reduction of the number of cardiovascular experiences and therefore the healthcare costs related to such experiences. However attempt is not made to express as a value the benefits from the introduction of the new technology cost - benefit analysis. This analysis is not applicable to the particular medicinal product and therefore it is not presented. 2. The pharmacoeconomic analysis takes into account the health perspective for the institution, which pays for the relevant therapy with public funds or the public perspective. The model has been developed from the viewpoint of the payer - the National Health Insurance Fund in Bulgaria. Only the direct expenses of NHIF are use, respectively upon 25% reimbursement of statins and 50% reimbursement of the fixed combination ezetimibe/ atorvastatin. 3. The time horizon of the pharmacoeconomic analysis is such that it allows reasonable and justified conclusions concerning the assessment of costs and the results compared to alternative technologies. The time horizon for the development of the pharmacoeconomic analysis is 40 years, which is considerably longer period than the one, which is usually used. This is due to the specificity of the examined technology i.e. that it is directed mainly to prophylaxis of chronic patients. 4. When it is necessary to extrapolate the results outside the time horizon of the clinical trials as well as for assessment of the results in the real practice, other models are used. 29

30 Not available. 5. When analysis is from the viewpoint of the society, both direct and indirect medical expenses are included. Expenses are presented that accompany the therapy of patients receiving statins and the new drug. The next table of the report displays the expenses for Atozet that would be made by NHIF per patient, per day, per month and per year. Table. Expenses for ezetimibe 10 mg/ atorvastatin 20 mg in Bulgaria per person Statin, dose (mg) / day* / month / year Ezetimibe 10 mg/ atorvastatin 20 mg The price for the three fixed combinations of Atozet is the same therefore the monthly therapeutic course paid by NHIF per patient is BGN 46,35 (23,70 ), respectively for one year it is BGN 556,20 (284,28 ). The table table below shows analogically the expenses for atorvastatin and rosuvastatin, from the viewpoint of the payer NHIF. Note the significantly lower expenses for the use of these drugs on monthly and annual basis. Table. Costs for statins in Bulgaria Statin, dose (mg) / day* / month / year Atorvastatin Rosuvastatin 10 mg Analysis is also made of additional expenses connected with prophylaxis of experiences and expenses incurred after a specific experience. Data are presented in the tables below. Expenses are indicated for hospitalization in case of acute insult, visits to the family doctor or to specialist/ cardiologist, the value of additional drugs after stroke and etc., but it is not clear whether these additional expenses are equal upon application of different drug therapies. 30

31 Table. Expenses connected with prophylaxis of experiences and expenses incurred after a specific experience. Base Min Max Source: Acute insult Hospitalization IS without and with thrombosis Visit to the family doctor for 6 months as in the price list of NFA for 2016 Visit to specialist/ cardiologist for 6 months as in the price list of NFA for 2016 Lipid panel for 6 months as in the price list of NFA for 2016 Liver panel for 6 months as in the price list of NFA for 2016 Additional drugs after insult month therapy as reimbursed by the Hospital fund - Clopidogrel, Bisoprolol, Ramipril, and rosuvastatin 20 mg Table. Expenses according to the health status COSTS on annual basis Module Base Primary No experience 0.00 Non-CVD death 0.00 Fatal CHD 0.00 Fatal insult 0.00 Acute CHD 0.00 Acute stroke 0.00 History of CHD No experience 1, Non-CVD death 0.00 Fatal CHD 2, Fatal stroke 1, Acute CHD 3,

32 Acute Stroke 2, History of stroke No experience Non-CVD death 0.00 Fatal CHD 2, Fatal stroke 1, Acute CHD 3, Acute stroke 2, History of CHD and stroke No experience 1, Non-CVD death 0.00 Fatal CHD 2, Fatal stroke 1, Acute CHD 3, Acute stroke 2,

33 Indirect expenses, which are incurred or saved by the new technology versus the conventional therapy are not analysed because according to the authors of the report the analysis is prepared only from the viewpoint of the payer - NHIF (according to the guidelines for assessment of health technologies in Bulgaria) and this perspective does not suggest that indirect expenses are included in the analysis. 6. Future expenses and results are discounted respectively by 5%. Discounting of effects and health effects with discount rate of 5.0% on annual basis is applied. Calculations are made for a cohort of patients at the age of 60, separately for the male and female population because significant differences are observed with regard to incidence of cardiovascular experiences between genders. As for the model that analyses the preventive therapy is used longer time horizon - 40 years, it is presumed that it traces all expenses and effects from the therapy during the whole life of the cohort of patients at the age of 60. Thus the model analyses sufficiently long period of time to track the risk of occurrence of coronary heart disease, cardiovascular disease and stroke. 7. The benefits from the health technology as end health results are presented as follows: 7.1. life year gained (LYG); Data about this indicator have been analysed individually for the male and the female population respectively presented in part III.1.2. above. The data show that in both case the switching from rosuvastatin 10 mg to Atozet increases the life years gained for both genders. Increases is by 0,16 years for male and by 0,17 years for women. Although the increase is insignificant, it does not depreciates the efficacy of the new drug compared to the preceding therapeutic analogues quality adjusted life year (QALY); Data about this indicator individually for the male and the female population are presented in part III.1.2. above. The presented results show increase in QALYs for both scenarios, respectively 0,15 for men and 0,16 for women. Patients treated with Atozet have more life years of higher quality - QALYs versus patients treated with rosuvastatin 10mg in case of lacl of data for end results, interim data are provided. Not applicable. 8. Sensitivity analysis is performed and sustainability of results is tested. 33

34 Data for sensitivity and sustainability of results are analysed by using unidirectional and probabilistic analysis individually for the male and the female population. The unilateral analysis of sensitivity for both scenarios has proven the sensitivity of the variable CHD with regard to the reduction of frequency, severity of services and the initial risk. Figure. Probabilistic analysis fo sensitivity ICER Figure. PSA Acceptability Plot 34