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Early benefit from structured care with atorvastatin in patients with coronary heart disease and diabetes mellitus: a subgroup analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study |
Athyros V G, Papageorgiou A A, Symeonidis A N, Didangelos T P, Pehlivanidis A N, Bouloukos V I, Mikhailidis D P |
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Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology The effect of structured care of dyslipidaemia with atorvastatin (strict implementation of guidelines) versus usual care (physician's standard of care) was examined. In the structured care group, the starting dosage of atorvastatin was 10 mg/day. If the National Cholesterol Education Program (NCEP) low-density lipoprotein cholesterol (LDL-C) goal of less than 2.6 mmol/L (100 mg/dL) was not reached within 6 weeks, the dosage was increased to 20 mg/day. With evaluation every 6 weeks, the dosage of atorvastatin was titrated up to 80 mg/day for patients not reaching the LDL-C goal with lower dosages. Patients on usual care were treated according to their physician's standard of care. Usual care included lifestyle changes (e.g. low-fat diet, weight loss and exercise), plus all necessary drug treatments and the use of lipid-lowering agents. Atorvastatin was not excluded from the usual care group.
Type of intervention Treatment and secondary prevention.
Economic study type Cost-effectiveness analysis.
Study population The study population comprised patients with CHD and diabetes mellitus. The inclusion criteria were:
established CHD (i.e. a history of myocardial infarction or 70% stenosis of at least one coronary artery, as documented by a coronary angiogram);
age less than 75 years;
an LDL-C level of greater than 2.5 mmol/L (100 mg/dL); and
a triglyceride (TG) level of less than 4.5 mmol/L (400 mg/dL).
Patients with recent acute coronary syndromes were not excluded. The exclusion criteria included renal or liver dysfunction, prior hypolipidaemic treatment, childbearing potential, and scheduled coronary revascularisation. Also excluded were patients with any significant disease likely to limit life to less than the duration of the study, such as malignancies and heart failure (New York Heart Association Class III or IV). By protocol, patients with liver enzymes greater than three times the upper limit of normal, serum creatine kinase 5 to 10 times the upper limit of normal, or persistent myalgia without serum creatine kinase elevation, were removed from the study.
Setting The setting was primary and secondary care. The study was carried out in Greece.
Dates to which data relate The authors reported that they had started to recruit patients 6 years before the publication of their article (2003). The recruitment was completed within a 2-year period. The year to which the prices and costs related was not reported.
Source of effectiveness data The effectiveness data were derived from a single study.
Link between effectiveness and cost data The costing was undertaken on the same patient sample as that used in the effectiveness study.
Study sample No sample size seems to have been determined in the planning phase of the study, and no power calculations were retrospectively performed. During the 2-year enrolment period, 1,600 eligible patients were enrolled (800 in each group). Of these, 313 (around 20%) had dyslipidaemia, of which 161 were in the structured care arm and 152 in the usual care arm. In the structured care group, 89 (55%) patients were males and 72 (45%) were females, and the mean age was 55 (+/- 11) years. In the usual care group, 87 (57%) patients were males and 65 (43%) females, and the mean age was 56 (+/- 12) years.
Study design The study was a randomised controlled trial that was carried out in several centres. The patients were randomised to either the structured care group, followed up by the University Clinic, or the usual care group, followed up by heart specialists, diabetologists, or general practitioners of the patient's choice outside the hospital. Randomisation was conducted using a computer-generated list (Random Number Generation, Statgraphics). After dose titration, the patients were followed up for a mean 3-year period with visits every 6 months. The authors explicitly reported that no patient from either treatment group was lost to follow-up.
Analysis of effectiveness An intention to treat analysis of all patients randomised to the structured care or usual care groups was performed. The main outcomes used were all-cause and coronary mortality, coronary morbidity (nonfatal myocardial infarction, revascularisation, unstable angina, and heart failure), and stroke. Other end points were the safety and efficacy of long-term treatment with atorvastatin. In both groups, physical and laboratory investigations for side effects were performed at weeks 6, 12 and 25, and every 6 months thereafter. After an overnight fast, total cholesterol, high-density lipoprotein cholesterol (HDL-C), TG, serum creatinine, and serum uric acid were assessed using an Olympus AU 560 auto analyser and respective reagents (Olympus Diagnostica GmbH). The LDL-C concentration was calculated using the Friedwald formula. At analysis, both groups were shown to be comparable in terms of their demographic characteristics, baseline CHD risk factors, concomitant drug treatment, glycaemic and arterial blood pressure control, and smoking status.
Effectiveness results During the mean 3-year duration of the study, 46 (30.3%) patients in the usual care group had a major vascular event or died versus 20 (12.5%) on structured care. The relative risk reduction (RRR) was 58%, (p<0.0001).
The RRR was 52% for all-cause mortality, (p=0.049), 62% for coronary mortality, (p=0.042), 59% for coronary morbidity, (p<0.002), and 68% for stroke, (p=0.046).
The RRR was 62% for nonfatal myocardial infarction (Q and non-Q wave), (p=0.042), and 64% for coronary revascularisation, (p=0.046).
The event rate curves for all events and for hard end points (coronary death, nonfatal myocardial infarction and revascularisation) started deviating from the sixth month of the study.
In the structured care group, all patients received atorvastatin. Three (1.86%) patients discontinued atorvastatin for personal reasons, but were still included in the analysis.
In the usual care group, only 46 (30%) patients received hypolipidaemic drug treatment, with a further 20 patients (13%) discontinuing this treatment after 6 to 8 months. Hence, only 26 (17%) patients were taking hypolipidaemic drugs for at least one year at any point during the study.
No significant modification in lipid profile values was recorded in the usual care group. Atorvastatin had a beneficial effect on total cholesterol, LDL-C, HDL-C, non-HDL-C, and TGs. Differences in lipid parameters between the usual care and the structured care groups were significant. The NCEP LDL-C treatment goal was reached by 150 (93%) patients on structured care compared with 6 (4%) patients on usual care.
During the study, 52 (34%) patients in the usual care group had desirable HDL-C levels (>40 mg/dL) versus 126 (78%) of those in the structured care group, (p=0.0004).
During the study, 17 (11%) patients in the usual care group had desirable TG levels (<150 mg/dL) versus 110 (68%) of those in the structured care group, (p<0.0001).
Patients on atorvastatin presented an 11% reduction in serum creatinine levels, from 97 (+/- 5) micromol/L to 86 (+/- 3) micromol/L, (p<0.0001). Usual care patients showed a 5% increase in serum creatinine levels, from 95 (+/- 5) micromol/L to 100 (+/- 4) micromol/L, (p=0.003).
Usual care patients presented an increase in serum uric acid levels by 4.4%, (447 +/- 58 versus 428 +/- 51 micromol/L; p<0.0001), while structured care patients had an 8.2% reduction in serum uric acid levels (393 +/- 42 versus 432 +/- 54 micromol/L; p<0001).
Thus, in the current setting, the authors estimated that 6 patients of the structured care group needed to be treated for 3 years to avoid an event of any kind. Eight patients needed to be treated to avoid one nonfatal vascular event, and 26 patients to avoid one death from any cause.
Clinical conclusions The results of the study showed that, compared with usual care, structured active management of dyslipidaemia with atorvastatin in patients with CHD and diabetes mellitus contributed to a significant and early reduction in mortality, coronary morbidity and stroke.
Modelling A Markov model was used to estimate the total costs of therapy and effectiveness (life expectancy) over time.
Measure of benefits used in the economic analysis The measure of benefits used was the number of life-years gained (LYG).
Direct costs The costs and the quantities were not reported separately. It appears that the direct costs to the health care system have been included in the analysis. The authors reported only that the total costs of therapy (including the treatment of CHD) were included in the analysis. They did not report which items this covered. In addition, the authors reported only that the costs were calculated on the basis of current retail drug prices and the cost of treatment for CHD-related adverse events in Greece. However, they did not report the sources used. It was also unclear whether the authors discounted the costs. The study only reported the synthesis of the costs and benefits (i.e. the incremental cost-effectiveness ratio, ICER). The total costs incurred by each group were not reported. The price year to which the costs referred was not reported.
Statistical analysis of costs No statistical analysis of the costs appears to have been performed.
Indirect Costs The indirect costs were not included in the analysis.
Currency US dollars ($). The exchange rates used were not reported.
Sensitivity analysis No sensitivity analysis was performed.
Estimated benefits used in the economic analysis The authors did not report the number of LYG for either group. As with the costs, the authors only reported the ICER.
Cost results The study only reported the synthesis of the costs and benefits (i.e. the ICER). The total costs incurred by each group were not reported.
Synthesis of costs and benefits The costs and benefits were combined by calculating a cost-effectiveness ratio (i.e. the additional cost required per LYG). When considering only direct medical expenses, the cost per LYG with structured care was $6,200.
Authors' conclusions Structured active management of dyslipidaemia can help patients with coronary heart disease (CHD) and diabetes mellitus to achieve National Cholesterol Education Program (NCEP) treatment goals, and provide health benefits in terms of morbidity and mortality. Statin treatment was cost-effective in the secondary prevention of CHD in patients with diabetes mellitus.
CRD COMMENTARY - Selection of comparators A justification was given for the comparator used. Physicians in Greece do not prescribe statins in the belief that CHD patients are not exposed to as high a risk as data from other Western countries suggest. You should decide if this is a widely used intervention in your own setting.
Validity of estimate of measure of effectiveness The basis of the effectiveness analysis was a randomised controlled trial, which was appropriate for the study question. In addition, well-conducted randomised controlled trials are the 'gold' standard design when comparing different health interventions. The study group was representative of the study population. The patient groups were shown to be comparable at analysis in terms of their demographic characteristics, baseline CHD risk factors, concomitant drug treatment, glycaemic and arterial blood pressure control, and smoking status. The statistical techniques used were appropriate. The analysis of effectiveness was handled credibly, with the outcomes being analysed on an intention to treat basis and clinical benefit being recorded in the absence of other interventions that may have favourably influenced the outcomes. Further, all differences in outcomes between the two groups were tested for significance using appropriate statistical techniques. The method of randomisation for each group was also reported and was conducted satisfactorily. Overall, the internal validity is likely to be high.
Validity of estimate of measure of benefit The estimation of the benefits used in the economic analysis (i.e. LYG) was modelled. However, the authors did not report the actual number of LYG for each group.
Validity of estimate of costs Due to the lack of information supplied by the authors, it was unclear whether all the relevant categories of cost were included in the analysis. It was also impossible to say if relevant costs were omitted from the analysis. Hence, it is not possible to state with certainty whether any omissions could have affected the authors' conclusions. All these factors will limit the generalisability of the authors' results. It was also unclear whether uncertainty in the cost data was investigated using appropriate statistical techniques. The authors failed to report the dates and exchange rates used to perform the currency conversions, which again will limit generalisability to other settings. Also, it was unclear whether the costs were discounted, even though this was necessary. The lack of detailed reporting makes it impossible to assess the quality of the cost analysis.
Other issues The authors made appropriate comparisons of their findings with those from other studies that also found beneficial outcomes in those patients receiving statins. The issue of generalisability to other settings was not addressed, and will be seriously hampered by the lack of information on the cost data and cost results. The authors do not appear to have presented the effectiveness results selectively. The authors' conclusions reflected the scope of the analysis. Only one limitation of the study was reported, the fact that it was not placebo-controlled. This was due to ethical and practical reasons. The main goal of the study was to assess clinical benefit from NCEP guideline implementation in comparison to that seen with real life treatment.
Implications of the study The authors recommended that, in view of the benefits conferred by structured active management of dyslipidaemia, urgent steps should be taken to convince all physicians of the benefits of cost-effective statin treatment in secondary CHD prevention.
Bibliographic details Athyros V G, Papageorgiou A A, Symeonidis A N, Didangelos T P, Pehlivanidis A N, Bouloukos V I, Mikhailidis D P. Early benefit from structured care with atorvastatin in patients with coronary heart disease and diabetes mellitus: a subgroup analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study. Angiology 2003; 54(6): 679-690 Other publications of related interest Hay JW, Yu WM, Ashraf T. Pharmacoeconomics of lipid-lowering agents for primary and secondary prevention of coronary artery disease. Pharmacoeconomics 1999;15:47-74.
Jonsson B, Cook JR, Pedersen TR. The cost-effectiveness of lipid lowering in patients with diabetes: results from the 4S trial. Diabetologia 1999;42:1293-301.
Indexing Status Subject indexing assigned by NLM MeSH Anticholesteremic Agents /therapeutic use; Atorvastatin Calcium; Coronary Disease /complications /prevention & Diabetes Complications; Diabetes Mellitus /drug therapy; Female; Heptanoic Acids /therapeutic use; Humans; Male; Middle Aged; Prospective Studies; Pyrroles /therapeutic use; Time Factors; control AccessionNumber 22003001561 Date bibliographic record published 30/11/2004 Date abstract record published 30/11/2004 |
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