UBC Faculty Research and Publications

Appraising the evidence : effectiveness of cholesterol testing and treatment in primary prevention. Kazanjian, Arminée, 1947-; Savoie, I. (Isabelle), 1965- Oct 31, 1997

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Centre for Health Servicesand Policy ResearchAPPRAISING THE EVIDENCE:EFFECTIVENESS OF CHOLESTEROL TESTING ANDTREATMENT IN PRIMARY PREVENTIONArrnlnee KazanjianIsabelle SavoieBCOHTA 97:16C OCT 1997B.C. Office of Health Technology AssessmentDiscussion Paper SeriesTHE UNIVERSITY OF BRITISH COLUMBIAAPPRAISING THE EVIDENCE:EFFECTIVENESS OFCHOLESTEROL TESTING ANDTREATMENT IN PRIMARYPREVENTIONArmlnee Kazanjian, Dr SocIsabelle Savoie, MD, MHAB.C. Office of Health Technology AssessmentCentre for Health Services & Policy ResearchS-184 - Koerner Pavilion, 2211 Wesbrook MallThe University of British ColumbiaVancouver, B.C. V6T 1Z3Presented at the 2nd International Conference Scientific Basis of Health Services &5th Annual Cochrane Colloquium, held in Amsterdam, October 5-12,1997.BC Office of Health Technology AssessmentConference PaperOctober 6, 19971.0 BackgroundIn the U.S. last year, $2.5 Billion was spent for the purchase of cholesterol lowering drugs.Cholesterol lowering drugs were the third most purchased after anti-ulcerant and calciumblocking agents. Over the past decades, there has been a lot of interest in using these drugs forthe primary prevention of coronary heart disease. However, successes with drugs like niacin,colestipol, clofibrate, and gemfibrozil have been limited. First, because of the poor tolerability ofmany these drugs. Drugs like niacin may produce significant gastro-intestinal malaise thatseriously affect their acceptability to patients.' Second, because of the finding of even moreserious side effects especially with clofibrate and gemfibrozil. Clinical trials of these drugs havefound them to produce significant increases in non-coronary heart disease (CHD) mortality.Increases which offset any benefits on the incidence of myocardial infarction (MI). 2-3The publication of a new trial at the end of 1995, the West of Scotland Coronary PreventionStudy Group (WOSCOpS),4 seemed to offer the much awaited evidence supporting a moreextensive use of cholesterol lowering drugs in primary prevention. The WOSCOPS trialevaluated a new drug; pravastatin. The trial reported a significant reduction in the incidence ofmyocardial infarction and cardiovascular deaths. This study has since been used to justify boththe testing and treatment of individuals without established coronary artery disease.2.0 PurposeThe purpose of this presentation is: i) to examine and discuss specific issues regarding thegeneralizability of the WOSCOPS trial; and, ii) to discuss the effectiveness of the cholesteroltesting strategies to identify patients who may benefit from pravastatin.BC Office of Health Technology AssessmentConference PaperOctober 6, 19973.0 The WOSCOPS trialThe West of Scotland trial is a double-blind trial which randomized 6,595 participants topravastatin or placebo and followed them for an average of 4.9 years. The primary clinicalendpoint was combined non-fatal myocardial infarction and CHD death. Participants wererecruited from coronary screening clinics through the West of Scotland district.After 5 years of treatment, the study reported absolute treatment effect ranging in size from 0.7%for cardiovascular deaths to 2.5% for the primary combined clinical endpoint. These findingswere statistically significant for p<O.01.Extrapolation and application of these findings to other populations, first require examination ofthree main issues regarding the generalizability of this trial.4.0 Generalizability of the trial4.1 Risk levelThe population of the West of Scotland district is known for having the highest world-wide riskof death from ischemic heart disease. The mean ischemic heart disease mortality rate for thatpopulation is estimated at 4.6 deaths per 1000 population per year. From this population, theinvestigators selected middle-aged men with average cholesterol level > 7.0 mmol/l. Based ondata from the British Heart Study, this would correspond to the top 20th percentile of the totalcholesterol distribution.' In addition, the study did not exclude patients with stable angina. Infact, 16% of the study sample is comprised of individuals with established coronary heart disease.In order for the results to be generalizable, these characteristics of the West of Scotland studysample first need to be contrasted with the incidence of ischemic heart disease in the Canadianpopulation. In the general Canadian population, the mortality rate from ischemic heart disease isaround 1.93 death per 1000 per year." Almost two and a half times less than that observed in theWest of Scotland study. In fact, the incidence of ischemic heart disease mortality in the West of2BC Office of Health Technology AssessmentConference PaperOctober 6,1997Scotland study sample is closer to that of individuals with established coronary heart disease.Meta-analyses of cholesterol lowering drugs have suggested that the benefit-risk ratio is likely tobe positive only in groups with an incidence ofCHD death ;;::: 3 deaths per 100 per year," Theyfurther suggested that this risk level was compatible with individuals with established coronaryheart disease, not with primary prevention population. Generalization of the WOSCOPS resultsto true primary prevention population would therefore involve using pravastatin in groups at arisk level lower than the 3% CHD deaths and may actually lead to a negative benefit-risk ratio.4.3 Understanding the risk levelNot only are the WOSCOPS participants at a higher risk for IHD, but the reasons explaining thisgreater risk are not fully understood. The reported incidence of CHD risk factors in theWOSCOP study sample is not significantly different from the incidence of the same risk factors ina Canadian population." Only differences in the number of smokers were documented but thesewere likely due to differences in case definition. The MONICA study (WHO) suggests thatknown risk factors explained at most 23% of the deaths from IHD.8 Until we obtain a betterunderstanding of the factors at play in the WOSCOPS study sample, the reproducibility of theseresults may not be possible.4.3 Gender issuesWhile few women were included in secondary prevention trials of cholesterol lowering drugs, thedata on primary prevention of coronary heart disease in women is even sketchier. The studysample of the WOSCOPS trial included only men and therefore provided no additional evidence inwomen. To date, the few primary prevention trials that have included women, have found nosignificant reductions in coronary heart disease morbidity or mortality from cholesterol loweringdrugs, including hormone replacement therapy." In addition, women have been shown to differfrom men in terms of their risk for CHD. It was estimated that in women, the risk of CHD issignificantly lower than that of men of the same age." Although women have increasinglydemanded and been provided with cholesterol testing and lowering interventions, the WOSCOPS3BC Office of Health Technology AssessmentConference PaperOctober 6. 1997study provides no evidence to support these measures. The effectiveness of cholesterol loweringintervention in women still remains to be demonstrated. The lower level of CHD risk in women isan important factor to consider in the benefit-risk ratio.5.0 Identifying patients for treatmentEven if the generalizability of the West of Scotland trial was not an issue, the matter of identifyingpatients that could benefit from pravastatin would be. To date, despite the serious issues aroundgeneralizability, policy-makers and guideline-developers have relied on the results of theWOSCOPS trials and have implemented testing strategy to identify candidates for treatment. Inthe U.S. for example, the recommendations of the U.S. Preventive Task Force and AmericanCollege of Physicians support testing of all middle-aged men and women without establishedcoronary heart disease.":" In Canada, groups like the Canadian Working Group and theSaskatchewan Health Services Utilization and Research Commission have also relied on theWOSCOP to support cholesterol testing in middle-aged men and women without establishedcoronary heart disease. 13-14However, these guidelines ignore the fact that in primary prevention population, total cholesterolis a poor predictor of CHD. Figure 1 illustrates the distribution of total cholesterol levels in menwith and without CHD. The figure emphasize the great amount of overlap between the twodistributions.' This amount of overlap results in a large number of false positive tests. A largenumber of men will test positive although they will not develop CHD. A review of the sensitivity,specificity and predictive value of lipid tests revealed that in a primary prevention population, thepositive predictive value for total cholesterol tests above 6.1 mmolll ranges from 1.6% (for anincidence CHD of 1.2% over 8 years) to 7.7% (for an incidence of CVD of 6.3% over 14years). 154BC Officeof HealthTechnology AssessmentConference PaperOctober 6, 1997Figure 1: Distribution of total cholesterol levels in men with and without lliD2 4 6 B 10In a Canadian setting, ifwe assume a total cholesterol sensitivity of 65%, a specificity of 80% anda positive predictive value as high as 16%, in a group of 100,000 men followed for 30 years,implementation of the U.S. Preventive Task Force, American College of Physicians orSaskatchewan's guidelines would lead to:• 22,555 men testing positive for high cholesterol;• 84% of these would be false positive;• 18,864 men would be treated though not at risk for MI or CHD death; and,• the incidence of MI and CHD death would be reduced from 5.7% to 5.6% over 30years.5.0 ConclusionThe generalizability of the WOSCOPS trial needs further examination before the study is used asto evidence to support cholesterol lowering and cholesterol testing in primary prevention. Even ifthe generalizability was ever established, the identification of patients eligible for treatment wouldstill be an issue. Given the poor predictive value of cholesterol testing and the small absolutetreatment effect obtained with pravastatin, in a true primary prevention population, theeffectiveness and cost-effectiveness of cholesterol testing and treatment program needs carefulexamination.5BC Office of Health Technology AssessmentConference PaperOctober 6, 19971 Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, et al.. for the Coronary Drug ProjectResearch Group. Fifteen year mortality in Coronary Drug Project patients: long-term benefits with niacin. JAmColI Cardiol1986;8(6): 1245-55.2 Frick MH, Elo 0, Haapa K, Heinonen OP, Heinsalmi P, Helo P et al. Helsinki Heart Study: primary preventiontrial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, andincidence of coronary heart disease. NEngl J Med 1987;317:1237-45.3 Committee of Principal Investigators. WHO Co-operative trial on primary prevention of ischemic heart diseaseusing clofibrate to lower serum-cholesterol: mortality follow-up. Lancet 1980;2:379-85.4 Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW et al. Prevention of coronary heart diseasewith Pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333: 1301-7.5 Wald NJ, Law M, Watt HC, Wu T, Bailey A, Johnson AM et al. Apolipoproteins and ischemic heart disease:Implications for screening. Lancet 1994;343:75-9.6 Health Canada. Canadians and heart health. Reducing the risk. Ottawa, National health and welfare, 1995.7 Smith GD, Song F, Sheldon TA. Cholesterol lowering and mortality: the importance of considering initial levelof risk. Br Med J 1993 May;306(6889):1367-73.8 The World Health Organization MONICA project. Int J Epidemio11994;23:505-16.9 Savoie I, Bassett K, Kazanjian A. Supporting clinical practice guidelines development: An appraisal of existingcholesterol testing guidelines. BC Office of Health Technology Assessment 97:D, Vancouver, 1997.10 Weinblatt E, Shapiro S, Frank CWo Prognosis of women with newly diagnosed coronary heart disease: acomparison with course of disease among men. Am J Public Health 1973 Jul;63(7):577-93.11 Report of the US Preventive Task Force. Guide to clinical preventive services. 2nd ed. Media: Williams andWilkins; 1996. p. 15-38.12 American College of Physicians. Guidelines for using serum cholesterol, high-density lipoprotein cholesterol,and triglyceride levels as screening tests for preventing coronary beart disease in adults. Ann Int Med 1996 Mar1;124(5):515-517.13 The Canadian Working Group on Hypercbolesterolemia and Other Dyslipidemias. Detection and management ofhypercbolesterolemia. Ottawa, ON: University of Ottawa Heart Institute; 1995.14 Health Services Utilization and Researcb Commission. Cholesterol Testing and Treatment Guidelines.Saskatoon, SK The Commission, November 1995.15 Savoie I, Kazanjian A. Predictive Value of Lipid Testing in Asymptomatic Individuals With Risk Factors. B.C.Council on Clinical Practice Guidelines Cbolesterol Panel. May 1995.6

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