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Treatment and prevention of coronary heart disease by ...

  1. 1. TREATMENT AND PREVENTION OF CORONARY HEART DISEASE BY LOWERING SERUM CHOLESTEROL CONCENTRATION; THIRD CONSENSUS ‘CHOLESTEROL’
  2. 2. TABLE OF CONTENTSTREATMENT AND PREVENTION OF CORONARY HEART DISEASE BY LOWERINGSERUM CHOLESTEROL CONCENTRATION; THIRD CONSENSUS ‘CHOLESTEROL’ .......3 ABSTRACT ................................................................................................................................................................................3 INTRODUCTION .........................................................................................................................................................................4 INTERVENTION STUDIES ............................................................................................................................................................5 Angiographic studies............................................................................................................................................................5 Dietary intervention studies .................................................................................................................................................5 Statin intervention studies....................................................................................................................................................6 GUIDELINES BASED ON LITERATURE DATA ...............................................................................................................................7 Secondary prevention...........................................................................................................................................................7 Primary prevention ..............................................................................................................................................................8 Cost-effectiveness.................................................................................................................................................................9 CONCLUSION ..........................................................................................................................................................................10GUIDELINES AND COST ........................................................................................................13 ABSTRACT ..............................................................................................................................................................................13 INTRODUCTION .......................................................................................................................................................................13 THE BALANCE BETWEEN COSTS AND EFFECTS .......................................................................................................................13 WHO DECIDES? .......................................................................................................................................................................14 THE CONSENSUS GUIDELINE ..................................................................................................................................................15 LIMITATIONS OF COST-EFFECTIVENESS ANALYSES ................................................................................................................17 CONCLUSION ..........................................................................................................................................................................19WORKING GROUP..................................................................................................................21REFERENCES .........................................................................................................................22 2
  3. 3. Treatment and Prevention of Coronary Heart Disease By Lowering SerumCholesterol Concentration; Third Consensus ‘Cholesterol’ML Simoons and AF Casparie1AbstractTreatment and prevention of coronary heart disease by lowering serum cholesterolconcentration; third consensus ‘Cholesterol’For the second time the consensus text for lipid lowering therapy is revised. In angiographicstudies it was shown that a decrease in the total cholesterol as well as the low-densitylipoprotein cholesterol level results in a reduction of the progression of vascular disease.Furthermore, intervention trials demonstrated that therapy with cholesterol synthesis inhibitorsreduces not only both the cardiovascular and total mortality, but also other manifestations ofcoronary heart disease (CHD). Hypercholesterolaemia is treated with a low-fat diet andnormalisation of the weight. For individuals, this might result I a reduction of the risk formyocardial infarction or death and for the population in a decrease of the mean serumcholesterol concentration and the incidence of CHD. The indication for drug therapy is foundedon the expected effectiveness to reduce the incidence of (new manifestations of) CHD, whichis related to the level of the absolute risk of avascular disease. In persons without knownvascular diseases this risk is calculated from the total and high-density lipoprotein cholesterolratio, age sex, blood pressure, diabetes mellitus, and smoking. Treatment with cholesterolsynthesis inhibitors must be considered in (a) patients with familial hypercholesterolaemia; (b)all patients with a prior myocardial infarction or other symptomatic vascular disorders with atotal cholesterol concentration > 5 mmol/l and a life expectancy of at least 5 years; (c) personswith a combination of diabetes mellitus, hypertension, hypercholesterolaemia and high risk fordeveloping CHD, rising from 25% per 10 years at the age of 40 to 35-40% per 10 years at theage of 70 years, with a life expectancy of at least five years. If these guidelines are followed,the upper limit of the calculated cost-effectiveness is about NLG 40,000 = per life year gained.The working group judges this reasonable in comparison with other therapeutic interventions inthe Netherlands.1 On behalf of the preparing group, the members of which are mentioned at the end of this article. 3
  4. 4. Introduction In the second half of this century a clear association has been established betweenserum cholesterol concentrations (total cholesterol and more specifically low-densitylipoprotein (LDL) cholesterol) and the development of coronary heart disease (CHD). On thebasis hereof, it was assumed that lowering the average serum cholesterol concentration in thepopulation would lead to a decreased incidence of CHD, and for individuals to a decreased riskof developing CHD (primary prevention) or of repeated manifestations of CHD (secondaryprevention). This assumption was supported by epidemiological findings and has recently beenconfirmed by results from various intervention studies with angiographic endpoints, as well as5 large intervention studies with clinical endpoints. This lead to the revision of treatmentguidelines for an elevated serum cholesterol concentration, as described in the consensus‘Cholesterol’ from the Centraal Begeleidingsorgaan voor de Intercollegiale Toetsing (CentralInstitution for Inter-collegial review; CBO).1 2 The new guideline differs from previous guidelines in two ways. Firstly, it denotestreatment of the cholesterol concentration is indicated for people with an increased risk ofdeveloping or deteriorating CHD. Apart from cholesterol concentration, this risk is determinedby a large number of other factors. The cholesterol concentration itself is of limited significanceand has to be evaluated in view of other risk factors (primary prevention) or clinicalcharacteristics (secondary prevention). Secondly, it calculates which costs the guidelinecomprises and whether the costs per life year gained can be viewed as acceptable. This consensus text has been prepared by a working group with delegates from theprofessional groups and adjusted after the hearing of 12 December 1997, during which theworking group discussed it with other healthcare parties such as patient groups, healthinsurance companies, pharmaceutical companies, the Department of Public Health, Welfareand Sport, and political parties. In this article we summarise the consensus text. 4
  5. 5. Intervention studiesANGIOGRAPHIC STUDIESThe effect of a number of different interventions aimed at improving the lipid profile, especiallylowering the LDL-cholesterol concentration, on coronary disorders has been studied by meansof repeated coronary angiography. Various strategies to improve the lipid profile wereadministered: single medicament therapy, combination therapy, invasive life style changes andiliacal bypass surgery. One study was conducted entirely in the Netherlands (REGRESS);another one was co-ordinated from the Netherlands (MAAS).3 4 A meta analysis of these angiographic studies in over 3700 patients revealed that onaverage, the total cholesterol concentration decreased with 23%, the LDL concentration with31%, and the triglyceride concentration with 8%. The ‘high-density lipoprotein’ (HDL)concentration increased with 8% on average.5 In the intervention group, significantly lessprogression was found of the angiographic irregularities and more regression. This wasaccompanied by a reduced number of patients who, after an average of 3 treatment years,died or suffered a myocardial infarction. This reduction was from 7.3 to 5.4%, which signifies a26% decrease. The number of patients undergoing a coronary bypass operation orpercutaneous transluminal coronary angioplasty (PTCA) also decreased significantly.5 Thesefindings support the idea that lowering the cholesterol concentration results in a stabilised orreduced progression of the plaques in the coronary arteries and hence leads to a reduction ofcardiovascular complications.DIETARY INTERVENTION STUDIESA reduced consumption of saturated fat and the prevention of obesity in the entire population isof great importance, since most new patients with CHD cannot be recognised in advance aspeople with an increased risk. The adequate treatment of people with a high absolute risk forthe individual is desirable, but insufficient from the viewpoint of public health. The prevalenceof CHD can only be reduced substantially by moving the average total cholesterol level in thepopulation to a lower level. A meta analysis of 17 randomised dietary intervention studies with over 90,000 peoplerevealed that a cholesterol concentration reduction of 10% not only leads to a decreased 5
  6. 6. prevalence of CHD (odds ratio (OR)): 0.87; 95% confidence limits (CI95): 0.83-0.91), but also toa reduced total mortality (OR: 0.94; CI95: 0.89-0.99).6 In the reference group 2541 (5.5%)people were deceased or struck by a myocardial infarction and in the intervention group 2205(4.8%). The dietary interventions consisted mainly of a reduced consumption of saturated fatand an increase in that of multiple unsaturated fat. In the first place, the cholesterolconcentration can be reduced with a diet conform the ‘guideline healthy eating’.7 Furthermore,to people with hypercholesterolaemia (total cholesterol concentration > 8 mmol/l), an individualdiet can be given and complementary drug treatment can be prescribed. Extra considerationfor the consumption of vegetables, fruit and fish is necessary, as well. In view of the fact that adiet is tailored to the individual and involves changing the patient’s behaviour, it can beconsidered to refer a patient to a dietician. However, in practice to persist in such dietarypatterns in the long run proves difficult for the individual and successful in only a limitednumber of occasions.STATIN INTERVENTION STUDIESIn the past years, drug treatment of hypercholesterolaemia has changed drastically. The drugsthat used to be considered previously (anion-exchange resins, fibrates and nicotinic acid),have made way for new cholesterol-lowering drugs, the cholesterol synthesis inhibitors. Thesedrugs inhibit the hydroxy-methyl-glutaryl-co-enzyme-A-reductase, also known as ‘statins’.Statins reduce the LDL-cholesterol concentration with 20-40%, while the HDL-cholesterolconcentration increases with 5-10%. Treatment with statins is an important gain for patientswith familial and other types of severe hyperlipidaemia and it is indicated for these patients.The exact choice of drugs or combinations hereof depends on the nature and severity of thehyperlipidaemia. Since 1994 results of 5 large international studies have become available, in which, nextto a diet, 30,000 people in total were treated with statins or placebo (‘Scandinavian SimvastatinSurvival Study’ (4S), Cholesterol and recurrent events trial (CARE), ‘Long-term interventionwith pravastatin in ischemic heart disease’ (LIPID; A. Tonkin, written information, 1997)), ‘Westof Scotland coronary prevention study’ (WOSCOPS), and ‘Air Force/Texas coronaryatherosclerosis prevention study’ (AFCAPS; A. Golto, written information, 1997)).8-10 Theresults of these studies provide insight in the effect of cholesterol lowering in patients with CHD 6
  7. 7. and hypercholesterolaemia (4S),8 in CHD patients without hypercholesterolaemia (CARE andLIPID),10 or an average cholesterol concentration (AFCAPS), in whom CHD had not yet beendiagnosed. The results of these 5 studies were remarkably consistent. In patients with known CHD(4S, CARE, LIPID),8,9 and in people with an increased risk, but without manifest CHD(AFCAPS),10 the treatment with statins for the duration of approximately 5 years wasassociated with a clear and statistically significant decrease in the number of patients whodied, had a myocardial infarction or a stroke, or underwent a revascularisation procedure.Immediately after the start of treatment, a remarkable decrease in total and LDL-cholesterolconcentration occurred, but differences in the so-called cardiovascular ‘endpoints’ did notoccur until after on average 1 treatment year (range: 0.5-2 years). The treatment effects were relatively strong (the average reduction in the number ofpeople who died or suffered a myocardial infarction during the study was 24-31%), but inabsolute sense not that strong. The strongest effects were noticeable in those studies in whichthe chances of dying or suffering a myocardial infarction were the highest (4S, CARE,LIPID).8,9 Especially in the primary prevention studies, the effects were limited. In WOSCOPS, forexample, 5 year treatment of 100 subjects with mild hypercholesterolaemia who had not yetdeveloped CHD resulted in extra survival of one person, while 3 died and 96 people weretreated who would not have died without 5 years of treatment, either.10 Of those 96 there were2 who suffered a myocardial infarction despite the treatment, whereas treatment prevented thisin 2 other people. Therefore, the ‘gain’ after treating 100 people for 5 years was 3 extrasurvivors without a myocardial infarction. In the secondary prevention study, 4S, these effects were about 3 times as strong and 5years of treatment resulted in a reduction in mortality of 3.3% and a reduction in the number ofpeople suffering a myocardial infarction of 8.6%.8 Here, the ‘gain’ of 5 years of treatment for100 people was 9 extra survivors without a myocardial infarction.Guidelines based on literature dataSECONDARY PREVENTIONIn the angiographic an clinical studies mentioned, it has been demonstrated beyond any doubtthat lowering the total and LDL cholesterol concentration with cholesterol synthesis inhibitors 7
  8. 8. improves the prognosis for a large group of CHD patients and for people at an increased riskof developing CHD. Data from the various studies cover a period of approximately 5 years. Inpractice, however, treatment will be continued for a much longer period. On the basis ofextrapolation of available data it may be assumed that the largest gain is achieved with long-term treatment. With this, it should be noted that the true effect of treatment with statins formore than 10 years is not certain, neither regarding efficacy, nor for safety. For the indicationsof statins, the working group assumed the effect noted in the first 5 years continues in thesame magnitude with treatment that lasts longer. The working group advises to consider the administration of statins in all patients withcoronary disorders or other forms of atherosclerotic vascular disorders (table). Treatment withstatins is considered not sensible in people with a low LDL-cholesterol concentration <3.2mmol/l or a total cholesterol concentration <5.0 mmol/l. For, in the CARE study no treatmenteffect was seen for these values.9 Treatment is also ineffective in people with a limited lifeexpectancy, while the risk associated with a higher cholesterol concentration decreases atolder age.11 Therefore, to start treatment in men aged over 70 and women aged over 75 doesnot seem sensible, especially since no specific data are available about the effects of treatingelderly people.PRIMARY PREVENTIONThe chance of developing new cardiovascular complications in CHD patients is about 30-50%in 10 years. The risk for patients in the CARE study, for example, was 36% and in 4S 48% in10 years.8, 9 In people without manifest CHD and with an increased risk of developing thesediseases the working group considers a slightly more liberal indication area acceptable, forinstance a 25% chance in 10 years at an age of 40, going to 35-40% in 10 years for a 70-yearold. The most appropriate measure to estimate the risk of CHD based on lipidconcentrations is the ratio of the total and the HDL-cholesterol concentration. For, this ratioreflects the high risk with the combination of high total cholesterol or a high LDL cholesterolconcentration with a low HDL concentration. Apart from this, other risk factors should be takeninto account. The ‘coronary risk model’, based on the Framingham data,12 is the best predictorof risk with a sensitivity of 70% and a specificity of 82%. In this model, the yearly risk of CHD is 8
  9. 9. a function of age, gender, blood pressure, total- and HDL-cholesterol concentration ratio, andthe absence or presence of diabetes mellitus and smoking (figure).Table: Absolute Risk for the Development of Coronary Heart Disease in the Next 10 Years(See Table given on page 49 Of Cholesterol Guideline (In Dutch); men = mannen; women =vrouwen; jaar = year; niet = no; Explanation: Absolute risks (in %) for the development ofcoronary heart disease in the next 10 years for people without cardiovascular disease, whohave family members in the first degree <60 years of age with coronary heart disease and (or)diabetes mellitus and (or) (un)treated hypertension, calculated on the basis of the Framinghamrisk score. After the determination of a patient’s risk factors the total cholesterol–‘high density’lipoprotein (HDL)–cholesterol is calculated. Next, from the figure the absolute risk can be readfor different ages. For ages between the decades and in between measurements for the totalcholesterol-HDL ratio, an estimation for the absolute risk can be made by extrapolation. Theindication for statin treatment is given in red; in the orange boxes an indication exists fortreatment with statins if coronary heart disease is present in first degree family members aged< 60 years. The figure cannot be applied to people with cardiovascular disease (see table,under ‘secondary prevention’), a serum cholesterol concentration > 8 mmol/l and (or)triglyceride concentration > 4 mmol/l (see table) or an age >70 (men) or >75 (women))COST-EFFECTIVENESSSince besides patients with known vascular disorders, large groups without manifest CHDcould be eligible for preventive drug treatment and this treatment comprises considerablecosts, the working group’s opinion is that, when determining the indication, cost-effectivenessconsiderations should be involved. Dutch data are available only to a limited extent. Therefore,the working group has determined the cost-effectiveness of cholesterol lowering with statintreatment based on 3 studies of which the data had been published: 4S, CARE, (bothsecondary prevention) and WOSCOPS (primary prevention).8-10 For this analysis, Dutch costswere attributed to the reported events. Of LIPID and AFCAPS, which were presented for thefirst time in November 1997, insufficient detail was available at the time of preparation of thisreport for a similar analysis. The previously mentioned limit of a 10-year risk of death or myocardial infarction orstroke of 25% (based on middle-aged people) amounts to a cost-effectiveness of 9
  10. 10. approximately NLG 40,000.= per life year gained. Furthermore, next to a reduced mortality,cholesterol lowering results in a decrease in the number of non-fatal myocardial infarctions andstrokes. For a heart transplant, the costs per life year gained are approximately NLG 60,000.=,for a liver transplant NLG 80,000.= and for breast cancer screening NLG 30,000.=, with whichit should be mentioned that what is considered acceptable also depends upon the number ofpeople eligible for treatment or screening and on the period within which the effects areexpected. Compared to other programmes, the working group considers a cost-effectivenessratio of NLG 40,000.= / life year gained reasonable. The result of the cost-effectiveness analysis, therefore, supports the conclusionmentioned in the preceding section that treatment with cholesterol lowering medication assecondary prevention should be considered for all patients with known coronary, cerebral, orperipheral arterial vascular disorders, except when the total cholesterol concentration < 5.0mmol/l or the LDL-concentration is <3.2 mmol/l, and when life expectancy is less than 5 years,especially in the elderly. Treatment should also not be considered when manifest cardiacfailure, a significantly decreased left ventricular failure, or any other severe illness is present.Primary prevention through drug treatment can be recommended in people with a risk ofmortality or a myocardial infarction > 25% in 10 years for middle-aged people and >35%-40%in 10 years for elderly people and with a life expectancy of at least 5 years (age < 70 (men) or<75 (women), see figure). This comprises a large number of patients with diabetes mellitusand a limited number of risk factors for the development of CHD. The working group’s opinion is that the observed efficacy is a group effect of statins,which means all statins are expected to have the same effects and, possibly, side effects. Themedication applied in clinical trials with which sufficient experience has been gained, aresimvastatin and pravastatin in a daily dosage of 20 or 40 mg. Clinical trials with other statinsare currently being undertaken.ConclusionTo reduce the cholesterol concentration in the population and to reduce the risk of CHD, theworking group recommends a diet in accordance with the ‘guidelines healthy eating’ for theentire population. The risk of CHD also decreases noticeably when smoking is discontinued.The working group recommends all people with manifest vascular disorders and all people withan increased risk of developing these use a cholesterol lowering diet, do not smoke, and arephysically active. 10
  11. 11. Drug treatment, especially with cholesterol-synthesis inhibiting drugs, should beconsidered in (a) patients with familial hypercholesterolaemia (total cholesterol concentration >8 mmol/l); these patients should be referred to a specialist with experience in this area; (b) allpatients with a prior myocardial infarction or any other symptomatic vascular disorders with atotal cholesterol concentration > 5 mmol/l or an LDL-concentration >3.2 mmol/l and with a lifeexpectancy of at least 5 years; (c) people with a high absolute risk of developing manifestvascular disorders due to the presence of diabetes mellitus, hypertension, smoking and anelevated serum cholesterol concentration. This treatment is considered effective and cost-effective at a risk of 25% in 10 years at the age of 40 to 35-40% in 10 years at the age of 70. Inthese people, as well, treatment is only sensible if life expectancy is at least 5 years. 11
  12. 12. RECOMMENDED STRATEGY WITH RESPECT TO HYPERLIPIDEMIAPreventionsecondary (people with manifest cardiovascular disease): serum cholesterol >5 mmol/l and age <70 years (men) or <75 (women); prescribe statins; see under ‘treatment’.primary (people without cardiovascular disease): coronary hearth disease (CHD) in first degree family members <60 and (or) diabetes mellitus and (or) (un)treated hypertension: see figure.Diagnosticsanamnesis: determine risk factors for CHDphysical examination: determine blood pressure, xanthomes, xanthelasmata, arcuscorneae < 40 yearslaboratory tests: determine total cholesterol levels. If first result ≤5mmol/l: do notrepeat; if >5 mmol/l: determine total and ‘high density’-lipoprotein (HDL) concentrationand the ratio twice; if lipemic plasma: determine fasting triglyceride concentration aswell. Baseline value is the average of 2 total cholesterol – HDL cholesterol ratios. Todetect secondary hyperlipidemia: determine alanin aminotransferase (ALAT), gamma-glutamyl transferase (γGT), thyroid stimulating hormone (TSH); glucose and protein inurine.Treatmentprimary, secondary and familial hyperlipoproteinemia serum cholesterol concentration > 8 mmol/l and (or) triglyceride concentration > 4 mmol/l: refer to specialistother people provide counselling regarding risk factors; stop smoking, weight reduction in case of obesity; dietary advice in accordance with the ‘guideline healthy eating’ in case of familial hypercholesterolaemia, diabetes mellitus and (or) hypercholerolemia with significant obesity: prescribe individual dietary guidance in case of indication for statin: simvastatin 20-40 mg daily, pravastatin 20-40 mg daily, fluvastatin 40 mg daily, atorvastatin 10 mg daily or cerivastatin 0.1-0.2 mg daily. Check cholesterol concentration after 3 months; if ≤ 5 mmol/l: continue dosage; if > 5 mmol/l: double dosage (once) 12
  13. 13. Guidelines and CostAF Casparie, BA van Hout, and ML SimoonsAbstractThere is a growing interest in developing clinical guidelines which support the efficiency ofmedical care by weighting the potential benefits against the costs of interventions. In therecently developed Dutch guideline on reduction of serum cholesterol concentration a formalcost-effectiveness analysis is included. Based on epidemiological arguments a cost-effectiveness ratio of 40,000 Dutch guilders per life year gained was found. In comparison withother preventive health care programmes this amount was considered acceptable. In the pastphysicians have often taken costs into account in an implicit way when making clinicaldecisions. The results of the cost-effectiveness vary particularly with the costs of the usedstatins. In the past physicians have often taken costs into account in an implicit way whenmaking clinical decisions. However, in view of the increase in health care expenditures, it hasbecome the responsibility of physicians to take costs into account more explicitly. Clinicalguidelines with a cost-effectiveness analysis can be useful in helping physicians to provideefficient medical care.IntroductionThe second revision of the consensus ‘Cholesterol’ contains a formal cost-effectivenessanalysis.13 This is the first time cost considerations have played an explicit role in developing atreatment consensus guideline. In the working group and during the hearing regarding theguidelines, and probably for some time onwards, this consideration for cost aspects hascaused discussion.14The Balance between Costs and EffectsIn view of the increasing awareness of healthcare costs, government and insurers, but alsohealthcare professionals, emphasise the importance of guideline development to enhanceefficient prescribing.15 This involves the refinement of indications for treatment and effects thatbalance the costs to be made. Generally, costs can contribute to the guidelines in two ways. 13
  14. 14. First, a cost analysis can be performed; this comprises the financial consequences oftreatment according to the guidelines. One step further is the cost-effectiveness analysis, inwhich the costs to be made are viewed in the context of the expected effects and costs pereffect become apparent. This effect can be establishing a diagnosis, or increasing lifeexpectancy, or improving the quality of life. The major advantage of a cost-effectivenessanalysis is comparisons can be made between different types of care. According to aguideline, care is definitely cost-effective when with this care the same effect is obtained withfewer costs than with the usual care. However, a guideline will also denote care as cost-effective if, in view of the treatment effects, the costs are reasonable and the cost-effectiveness ratio is comparable with that of other, generally accepted treatments. Usually, insuch cases the number of life years gained or quality adjusted life years is taken as a measureof effect.Who decides?An example of where cost-effectiveness analysis would be appropriate is the treatment ofelevated cholesterol levels. On a population level, decreasing the cholesterol concentrationalmost always has some effect. Treatment of large groups, however, is accompanied withconsiderable costs. Therefore, it makes sense to give priority to people with a major increasedrisk of serious cardiovascular disease, since the effects gained will have a more profitable ratioto the costs made than with people who are at a lower risk. Immediately, two questions atwhich the discussion has been focussed come to mind: what is an acceptable ratio, casu quohow much may a life year gained cost, and who may or must determine this? Is this anindividual doctor’s task or the medical profession’s, or should ‘politics’ solve this issue? It wasgenerally indicated that, if limits must be given, this should happen at the macro level of policymakers and not at the bedside. However, in practice the distinction cannot always be madethat clearly. Doctors have always made choices between individual patients when the time andmeans available to them were at stake. At the other patients’ expense, one patient would begiven more time or some patients were treated more urgently than others. Usually, thishappened implicitly; apparently the problem arises when such choices are made explicit. Apartfrom this, doctors still assume some balance must exist between the effects gained and thecosts accompanying those effects. In the past, physicians have aimed at the most efficienttreatment possible to use the available means as well as possible and, in that way, be able to 14
  15. 15. help other patients as well. In short, also at the level of individual patients, costs have alwaysplayed a role in medical care, albeit an implicit one.Table 2.1. Cost per cardiovascular treatment or complicationtreatment or complication costs in NLG sourcesimvastatin (20 mg daily); 1,020 Farmacotherapeutisch Kompas 19972 (cost per year)pravastatin (40 mg daily); 1,820 Farmacotherapeutisch Kompas 1997 (cost per year)coronary bypass surgery 30,820 REGRESS, 199516PTCA 12,890 REGRESS, 19951non-fatal stroke 24,600 Limburg, 199617 x 0,753fatal stroke 7,980 Limburg, 19962 x 0,75†non-fatal myocardial infarction 14,450 REGRESS, 19951fatal myocardial infarction 3,320 Jönsson, 199618other cardiovascular death 2,000 estimateother death 2,000 estimatePTCA= percutaneous coronary angioplastyThe Consensus GuidelineThe consensus guideline recommends the consideration of treatment with cholesterol loweringdrugs, especially statins, for patients with familial hypercholesterolaemia, patients with knowncardiovascular disorders (secondary prevention), and patients with a significantly increasedrisk of cardiovascular disease (primary prevention), in each case when cholesterol levels arehigher than 5 mmol/l and life expectancy is at least 5 years. The working group recommendednot to prescribe statins to men over 70 and women over 75 years of age. This should not beseen as discrimination by age. The age limits mentioned were drawn, because no specific datawere available regarding treatment effects with statins in people aged over 70. Furthermore,there were signs that decreasing cholesterol at older age is less effective than at youngerage,19 whereas at age over 85 elevated levels are even associated with better survival.20Finally, research in younger patients demonstrates a clear effect and an acceptable cost-effectiveness ratio is only achieved after treatment for at least a number of years. Naturally,treatment that has been initiated before the indicated age limit should not be discontinuedwhen the age of 70 or 75, respectively, is reached. In the consensus guideline it was noted that recommendations which seemedappropriate on medical grounds, also were acceptable on the basis of the cost-effectiveness2 Dutch National Formulary; lists all available drugs in the Netherlands + costs + brief therapeutic guidance 15
  16. 16. analysis. This was using a limit of NLG 40,000.= (US $20,000.=) per life year gained, which isslightly higher than is accepted for screening for breast cancer and cervical cancer – for whichpreventive programs also exist. This led to a situation in which the cost-effectiveness analysiswas merely supportive for treatment and did not determine the guideline’s contents. Until nowit remains unclear what will happen when, with the development of a guideline, the clinical andeconomical angles lead to conflicting conclusions regarding what is or is not desirable.Possibly the future, in view of the minister’s contribution to give cost-effectiveness an explicitrole in guideline development, will tell. In line with this, the question how many patients areinvolved becomes important. For, for rare treatments an unfavourable cost-effectivenessbalance has far fewer consequences for society than when the treatment involves large patientgroups. In a commentary on the recently published national guideline on statin use in Englandthis problem has been addressed extensively.21 It was calculated that, according to thisguideline, 8.2% of the English population aged between 35 and 69 should be treated and thiswould account for 20% of the drug budget. The main criticism in this commentary focussed onthe complete absence of a cost-effectiveness analysis in the English guideline.3 assuming 75% of patients with a stroke is admitted to hospital 16
  17. 17. Figure 2.1 Costs per life year gained (free from myocardial infarction or stroke) as a function ofthe initial absolute risk. The horizontal line denotes a cost-effectiveness of NLG 40,000.=; thevertical lines indicate the 10-year risks as found in the studies. y-axis: cost-effectiveness (NLG) x-axis: 10-years risk of mortality/myocardial infarction/strokeLimitations of Cost-effectiveness AnalysesIncidentally, to calculate cost-effectiveness is no simple task. In this consensus guideline, firstit was determined what the desired effects, expressed as life years gained, comprised oftreatment with diet and medication in people with different initial risks. Subsequently, it wascalculated what the costs of medical treatment were and which costs could be saved due tothe diminishing frequency of cardiovascular disease leading to decreasing need ofcardiovascular diagnostic procedures and treatment. This analysis included direct medicalcosts only. As indicated previously, the calculation of cost-effectiveness of treatment alwaysinvolves the comparison with a reference scenario. In this case this was a scenario in which no 17
  18. 18. statins were prescribed at all. In this way the costs of NLG 40,000.= per life year gained werecalculated. In practice, currently many patients use statins already. If the indication for this isnot always correct, cost-effectiveness in the current situation might be less favourable thanthat in the care according to the guideline. Since the model contained quite a few assumptions, a sensitivity analysis wasperformed to see which factors had a relatively large impact on the final conclusion. It becameclear the statin price was an important factor in the determination of the cost-effectivenessratio. In case statin prices dropped, this ratio immediately would become more favourable.From this, it follows that when the drug prices differ, results of cost-effectiveness analyses mayvary from country to country. Furthermore, cost differences of staff and materials will also givea different result of such an analysis in different countries. Incidentally, one should be awarethat for many interventions the effects and costs are only partly known. On top of that, noconsensus exists regarding the types of effect and the costs to be considered in thecalculations and studies differ in this respect. This indicates the limited value of cost-effectiveness analyses, which also implies results of such analyses of different interventionscannot simply be compared to each other. This consensus text addresses guidelines that should support the individual doctor, inconsultation with the patient, with decision making under specific clinical circumstances. Nextto cost-effectiveness considerations, other factors are important such as the expectedconcordance and the considerations of medicalisation by prescribing medication to people whodo not feel ill. This makes the provision of care a matter tailored to the individual. Twice in recent years, cost-effectiveness analyses have been performed in relation toconsensus guidelines, but not until after the guidelines had been developed. For the guidelineof screening and treatment of diabetic retinopathy it was determined that for type 2 diabeticsthe suggested screening frequency would result in an increase in the number of years withoutvisibility complaints against lower costs, while for type 1 diabetics the guideline even resultedin cost savings compared to no screening or more frequent screening.22 For the guideline ondiagnostic conduct at the suspicion of pulmonary embolism it could be determined that,compared to the usual treatment, care according to the guideline resulted in 10% fewerdiagnostics.23 18
  19. 19. Figure 2.2 10-years risk of mortality, myocardial infarction or stroke in which treatment withstatins costs NLG 40,000.= per life year gained, by age and gender (unadjusted for an age-dependent treatment effect) y-axis: 10-years risk of mortality/myocardial infarction/stroke x-axis: age (years) ■ men ○ womenConclusionWhen treating individual patients, treatment costs should play a certain role. An immediateconsequence of this statement is, each doctor should strive for efficient conduct on the level ofthe individual, which implies working within the correct indication area, no means are utilisedunnecessarily, and the costs and consequences are at an acceptable level. Guidelines thatprovide insight in cost consequences of treatment or that contain a cost-effectiveness analysis,can provide support for that; however this excludes guidelines aiming at cost reductions incare. It is the medical profession’s responsibility to develop such guidelines. 19
  20. 20. Table 2.2 Cost-effectiveness of treatment with cholesterol lowering drugsnumber 4S24 4S CARE25 CARE WOSCOPS26 WOSCOPS simvastatin placebo pravastatin placebo pravastatin placebotreatment for 5 yearsaverage survival (in years) 4.80 4.75 4.76 4.75 4.92 4.89average survival without MI 4.47 4.30 4.52 4.46 4.79 4.72or stroke (in years)cost (NLG) 12,005 8,253 13,918 7,687 8,722 1,906cost per life year gained 70,011 241,8054 325,229(NLG)cost per life year gained 23,698 108,716‡ 110,659without MI or stroke (NLG)treatment for 10 yearsaverage survival (in years) 9.24 8.94 9.04 8.94 9.65 9.54average survival without MI 8.06 7.28 8.23 7.84 9.14 8.85or stroke (in years)cost (NLG) 22,626 16,639 25,476 15,407 16,391 4,090cost per life year gained 23,285 59,989‡ 131,074(NLG)cost per life year gained 8,885 30,269‡ 46,858without MI or stroke (NLG)lifelong treatmentaverage survival (in years) 20.19 18.29 18.66 17.34 23.71 22.97average survival without MI 13.28 10.37 14.47 12.94 19.68 17.66or stroke (in years)cost (NLG) 57,560 41,244 54,859 32,700 45,115 15,681cost per life year gained 11,804 19,570‡ 56,936(NLG)cost per life year gained 7,363 12,866‡ 19,418without MI or stroke (NLG)4 cost-effectiveness in the CARE study calculated for patients with an LDL concentration >3.2 mmol/l, so excluding patientswith an LDL concentration < 3.2 mmol/l in whom treatment with pravastatin was ineffective 20
  21. 21. Working GroupThe working group consisted of: dr AJ Azal, secretary, clinical epidemiologist, CentraalBegeleidingsorgaan voor de Intercollegiale Toetsing (CBO), Utrecht; P Bengel-ten Voorde,dietician, Roosendaal; dr CM Boersma-Cobbaert, clinical chemist, Rotterdam; dr H Bruins Slot,vascular surgeon, Goes; prof dr A Casparie, chair, Rotterdam; ir. SJ van Dis, dietary specialist,Nederlandse Hartstichting, Den Haag; BB van Drenth, general practitioner (GP), Wijchen; drJJE van Everdingen, secretary, CBO, Utrecht; AFM Haverkort, GP, Beuningen; dr BA vanHout, economist, Rotterdam; C Hulst, director Harlezorg, Epe; dr LWM Janssen, thoraxsurgeon, Utrecht; dr JW Jukema, cardiologist, Leiden; dr JJP Kastelein; internist, Amsterdam;prof dr JGP Tijssen, clinical epidemiologist, Amsterdam; prof dr ir FJ Kok, epidemiologist,Wageningen, prof dr ir D Kromhout, epidemiologist, Bilthoven; PM Rijke-van Zeijl, dietician,Waddinxveen; prof dr ML Simoons, chair, cardiologist, Rotterdam; dr AHM Smelt, internist,Leiden; prof dr AHF Stalenhoef, internist, Nijmegen, I Stoel, cardioloog, Dordrecht; prof dr SThomas, GP, Nederlands Huisartsen Genootschap (NHG), Utrecht; dr NJ Verhoef, clinicalchemist, Oosterhout; dr L Verschoor, internist, Arnhem; T van de Weijden, doctor-researcher,NHG, Utrecht. 21
  22. 22. REFERENCES1 Erkelens DW. Cholesterol-consensus in Nederland. Ned Tijdschr Geneeskd 1987;131:1564- 9.2 Erkelens DW. Herziening consensus cholesterol. Ned Tijdschr Geneeskd 1991;135:2337- 40.3 Jukema JW, Bruschke AVG, Boven AJ van, Reiber JHC, Bal ET, Zwinderman AH, et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995;91:2528-40.4 MAAS investigators. Effect of simvastatin on coronary atheroma: the Multicentre Anti- Atheroma Study (MAAS). Lancet 1994;344:633-8.5 Vos J. Retardation of progression of coronary atherosclerosis [dissertation]. Rotterdam: Erasmus Universiteit Rotterdam, 1997.6 Truswell AS. Review of dietary intervention studies: effect on coronary events and on total mortality. Aust N Z J Med 1994;24:98-106.7 Nader advies inzake de richtlijn mbt de vetconsumptie uit het advies Richtlijn Goede Voeding 1986. Voedingsraad. Den Haag: Voorlichtingsbureau voor de voeding, 1991.8 Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.9 Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:1001-9.10 Sheperd J, Cobbe SM, Ford J, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with hypercholesterolaemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301-7.11 Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? BMJ 1994;308:367-73.12 Grover SA, Coupal L, Hu XP. Identifying adults at increased risk of coronary disease. How well do the current cholesterol guidelines work? JAMA 1995;274:801-6. 22
  23. 23. 13 Simoons ML, Casparie AF. Behandeling en preventie van coronaire hartziekten door verlaging van de serumcholesterolconcentratie: derde consensus ‘Cholesterol’. Ned Tijdschr Geneeskd 1998;142:2096-101.14 Everdingen JJE van. Cholesterolverlaging als testcase voor macro-economische keuzen in de gezondheidszorg. Med Contact 1997;52:1573-4.15 Casparie AF, Everdingen JJE van, Grol RPTM, Klazinga NS, Kleijnen J, Loo M van het, et al. Ontwikkeling en implementatie van kosteneffectieve richtlijnen. Onderzoeksprogramma ‘Bevordering Doelmatig Handelen’ van start. Med Contact 1998;53:88-90.16 Jukema JW, Bruschke AVG, Boven AJ van, Reiber JHC, Bal ET, Zwinderman AH, et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995;91:2528-40.17 Kunnen patiënten met een CVA beter worden behandeld? Eindverslag ontwikkelingsgeneeskunde project OG 91_037. Amsterdam: Academisch Medisch Centrum, 199618 Jönsson B, Johannesson M, Kjekshus J, et al. Cost-effectiveness of cholesterol lowering: results from the Scandinavian Simvastatin Survival Study (4S). Eur Heart J 1996;17:1001-7.19 Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? BMJ 1994;308:367-72.20 Weverling-Rijnsburger AW, Blauw GJ, Lagaay AM, Knook DL, Meinders AE. Total cholesterol and risk of mortality in the oldest old. Lancet 1997;350:1119-23.21 Freemantle N, Barbour R, Johnson R, Marchment M, Kennedy A. The use of statins: a case of misleading priorities? BMJ 1997;315:826-8.22 Crijns H, Casparie AF, Hendrikse F. Toekomstige behoefte aan oogzorg voor patiënten met diabetes mellitus, kosten en effectiviteit. Ned Tijdschr Geneeskd 1995;139:1336-41.23 Michel BC, Seerden RJ, Beek EJR van, Büller HR, Rutten FFH. Kosten van diagnostiek en behandeling wegens longembolie lager door toepassing van de consensusstrategie. Ned Tijdschr Geneeskd 1996;140:1864-8.24 Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.25 Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average 23
  24. 24. cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:1001-9.26 Sheperd J, Cobbe SM, Ford J, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with hypercholesterolaemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301-7. 24

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