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Epidemiology studies: Concluding remarks
56
Fibrinolysis
Tests in Epidemiological
Studies
Edinburgh: Churchill Livingstone, 1993: 3 l-46. 2. Lowe GDO, Wood DA, Douglas JT et al. Relationships of plasma viscosity, coagulation and frbrinolysis to coronary risk factors and angina. Thtomb Haemostas 1991; 56: 339-343. 3. Lowe GDO, Fowkes FGR, Dawes J, Donnan PT, Lennie SE, Housley E. Blood viscosity, fibrinogen and activation of coagulation and leucocytes in peripheral arterial disease and the normal population in the Edinburgh Artery Study. Circulation 1993; 87 (In press). 4. Smith FB. Lowe GDO, Fowkes FGR, et al. Smoking, haemostatic factors and lipid peroxides in a population case control study of peripheral arterial disease. Atherosclerosis 1993, (In press). 5. Fowkes FGR, Connor JM, Smith FB, Wood J, DOMCHIFT. Lowe GDO. Fibrinogen genotype and risk of peripheral atherosclerosis. Lancct 1992,339: 693-696. 6. Rumley A, Ratttay A, Fowkes FGR, Elton R, Housley E, Lowe GDO. Prediction of coronary events and disease progression by plasma D-dimer antigen in patients with peripheral atterial disease. Thmmb Haemostas 1993 (In press). 7. Lee AJ, Smith WCS, Lowe GDO, Tunstall-Pedoe HD. Plasma fibrinogen and coronary risk factors: the Scottish Heart Health Study. J Clin Epidemiol 1990; 43: 913-919. 8 Lee AJ, Lowe GDO, Woodward M, Tunstall-Pedoe H. Fibrinogen in relation to personal history of prevalent hypertension, diabetes, stroke, intermittent claudication, coronary heart disease and family history: the Scottish Heart Health Study. Br Heart J 1993; 69: 338-342. 9. Lowe GDO, Smith WCS, Tunstall-Pedoe HD et al. Cardiovascular risk and haemorheology -results from the Scottish Heart Health Study and the MONICA Project, Glasgow. Clin Hemorheol 1988; 8: 5 17-524. 10 Lowe GDO, Lee AJ, Rumley A, Smith WCS, Tunstall-Pedoe HD. Epidemiology of haematocrit, white cell count, red ce!l aggregation and fibrinogen the Glasgow MONICA Study. Clin Hemorheol1992; 12: 535-544.
Epidemiology Studies: Concluding Remarks Fraqois Duckert Visiting Professor at the Laboratory for Thrombosis Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro, Italy Permanent address: Magnolienpark, 14,4052 Base& Switzerland
Recently epidemiology, the science which investigates the causes and control of epidemic diseases, has been extended to population studies, to clinical studies and even clinical trials. Epidemiology is in. It is apparently easy to accumulate results. However, it is not simple to reach outstanding quality and to avoid the numerous pitfalls associated with such studies and to arrive at sound conclusions. It is certainly recommended to be pessimistic when planning a study and to exaggerate precautions. AlI the painstaking efforts will be more than rewarded at the end of
the study evaluation. The number of subjects: normal person and/or patients to be investigated must be determined as a function of the study aims. Admission criteria and conditions of examination are never too carefully described. The prevention of a high rejection rate at evaluation time will increase the quality and eliminate bias. It is important to carefully record and characterize the non admitted patients and the causes of exclusion, thus avoiding a dangerous extrapolation of results obtained on few subjects to the entire population. If a benefit of 3% is obtained on patients representing only 10% of the overall patients population, the total benefit of the potential treatment will remain extremely low since most people wih never have the chance to be treated. Monocentric studies are also opposed to multicentric ones, Additional difficulties are produced by multicentric enterprises. They have, however, the advantage to reduce duration and to reflect better the daily life reality by mixing data from different centres and countries thus increasing the general validity of the study conclusions. This brings us to the question of locally or centrally performed laboratory work. Locally obtained data will be less homogeneous than centrally produced results. Nevertheless, active local participation will increase motivation and therefore quality. The results should not only be more widely accepted, they also will have a better impact in terms of prevention and treatment. Considering now more specific problems of studies involving an analysis of the haemostatic system - coagulation, fibrinolysis, platelet function and related properties - blood collection is a crucial point. The conditions must be exactly defined and strictly followed: fasting or non fasting subjects, day time, technique, amount and processing of blood. Deviations will automatically introduce variations and errors. Then the conditions of storage (snap freezing, temperature, tubes) as well as the number and volume of the plasma samples must be accurately described. The laboratory techniques must be specific, sensitive, precise, reproducible, simple and robust. The two last specifications are important when large numbers of tests have to be performed in a short period and in several centres. Also the work capacity of each centre must be carefully evaluated and the admission rate adapted to it Disregarding the local situation will introduce unnecessary and easily avoidable technical and psychological difficulties. Quality and comparability of results obtained in different centms must be established and permanently controlled. The use of standards for each parameter is by far not sufficient Cooperative studies have repeatedly shown how difficult it is to obtain identical results sometimes to get values in the correct order for samples with undiscutably established activities or concentrations obtained by simple dilutions. Quality controls must be regularly performed starting before testing the study samples and during its entire
Fibrinolysis
duration. They must be organized to make internal quality in a centre totally independent of other centres. Thus others can not be made responsible for a centre own deficiency. A way of dealing with insufficient quality must be devised in advance. It is never an easy task. into consideration these Taking general recommendations one may expect to get better results, more significant correlations and aim to better practical applications. The final goals of epidemiological studies may widely vary: .
find out the best possible treatment for a well defined group of patients
.
elucidate physiopathological problems resulting in potentially more efficient type of treatment
.
find predictive tests for patients at risk leading to selective prophylactic measures
.
modify life style for disease prevention.
The final goal of all types of studies is in some way the prolongation of life. This does not go without possible adverse consequences. The medical community is frequently reluctant to accept clear cut results of predictive tests indicating that patients will no more have even the smallest benefit of
57
any active treatment. Furthermore, the problem of an aging popillation is very serious. Is it beneficial for the society at large to save at high costs some patients with coronary heart disease when sixty years old or older thus increasing the financial load supported by the young active and continuously relatively decreasing part of the population? It is nice to prevent arteriosclerosis by diet only and by reducing smoking. However, this could very well be the source of socioeconomic problems. For example it is convenient to recommend olive oil as a good source of fat in Italy. It goes hand in hand with Italian tradition and economy. It may cause problems in other countries were lard is readily available and olive oil not on the market and not produced by the farmers. In this respect the mass media may increase the beneficial effect of epidemiological studies, thoughtless use of irreproachable data may have harmful consequences. In certain circumstances, as for the beneficial influence of moderate wine consumption it may be preferable to keep the findings secret in order to avoid an exaggeration of alcoholism which is by itself sufficiently deleterious. Thus it is fair to recommend a pessimistic approach to epidemiological studies if one wants to smile at the very end of the study. These remarks do not pretend to be original. The fact is that they are too frequently forgotten.
Fibrinolysis
Tests in Epidemiological
Studies
Edinburgh: Churchill Livingstone, 1993: 3 l-46. 2. Lowe GDO, Wood DA, Douglas JT et al. Relationships of plasma viscosity, coagulation and frbrinolysis to coronary risk factors and angina. Thtomb Haemostas 1991; 56: 339-343. 3. Lowe GDO, Fowkes FGR, Dawes J, Donnan PT, Lennie SE, Housley E. Blood viscosity, fibrinogen and activation of coagulation and leucocytes in peripheral arterial disease and the normal population in the Edinburgh Artery Study. Circulation 1993; 87 (In press). 4. Smith FB. Lowe GDO, Fowkes FGR, et al. Smoking, haemostatic factors and lipid peroxides in a population case control study of peripheral arterial disease. Atherosclerosis 1993, (In press). 5. Fowkes FGR, Connor JM, Smith FB, Wood J, DOMCHIFT. Lowe GDO. Fibrinogen genotype and risk of peripheral atherosclerosis. Lancct 1992,339: 693-696. 6. Rumley A, Ratttay A, Fowkes FGR, Elton R, Housley E, Lowe GDO. Prediction of coronary events and disease progression by plasma D-dimer antigen in patients with peripheral atterial disease. Thmmb Haemostas 1993 (In press). 7. Lee AJ, Smith WCS, Lowe GDO, Tunstall-Pedoe HD. Plasma fibrinogen and coronary risk factors: the Scottish Heart Health Study. J Clin Epidemiol 1990; 43: 913-919. 8 Lee AJ, Lowe GDO, Woodward M, Tunstall-Pedoe H. Fibrinogen in relation to personal history of prevalent hypertension, diabetes, stroke, intermittent claudication, coronary heart disease and family history: the Scottish Heart Health Study. Br Heart J 1993; 69: 338-342. 9. Lowe GDO, Smith WCS, Tunstall-Pedoe HD et al. Cardiovascular risk and haemorheology -results from the Scottish Heart Health Study and the MONICA Project, Glasgow. Clin Hemorheol 1988; 8: 5 17-524. 10 Lowe GDO, Lee AJ, Rumley A, Smith WCS, Tunstall-Pedoe HD. Epidemiology of haematocrit, white cell count, red ce!l aggregation and fibrinogen the Glasgow MONICA Study. Clin Hemorheol1992; 12: 535-544.
Epidemiology Studies: Concluding Remarks Fraqois Duckert Visiting Professor at the Laboratory for Thrombosis Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro, Italy Permanent address: Magnolienpark, 14,4052 Base& Switzerland
Recently epidemiology, the science which investigates the causes and control of epidemic diseases, has been extended to population studies, to clinical studies and even clinical trials. Epidemiology is in. It is apparently easy to accumulate results. However, it is not simple to reach outstanding quality and to avoid the numerous pitfalls associated with such studies and to arrive at sound conclusions. It is certainly recommended to be pessimistic when planning a study and to exaggerate precautions. AlI the painstaking efforts will be more than rewarded at the end of
the study evaluation. The number of subjects: normal person and/or patients to be investigated must be determined as a function of the study aims. Admission criteria and conditions of examination are never too carefully described. The prevention of a high rejection rate at evaluation time will increase the quality and eliminate bias. It is important to carefully record and characterize the non admitted patients and the causes of exclusion, thus avoiding a dangerous extrapolation of results obtained on few subjects to the entire population. If a benefit of 3% is obtained on patients representing only 10% of the overall patients population, the total benefit of the potential treatment will remain extremely low since most people wih never have the chance to be treated. Monocentric studies are also opposed to multicentric ones, Additional difficulties are produced by multicentric enterprises. They have, however, the advantage to reduce duration and to reflect better the daily life reality by mixing data from different centres and countries thus increasing the general validity of the study conclusions. This brings us to the question of locally or centrally performed laboratory work. Locally obtained data will be less homogeneous than centrally produced results. Nevertheless, active local participation will increase motivation and therefore quality. The results should not only be more widely accepted, they also will have a better impact in terms of prevention and treatment. Considering now more specific problems of studies involving an analysis of the haemostatic system - coagulation, fibrinolysis, platelet function and related properties - blood collection is a crucial point. The conditions must be exactly defined and strictly followed: fasting or non fasting subjects, day time, technique, amount and processing of blood. Deviations will automatically introduce variations and errors. Then the conditions of storage (snap freezing, temperature, tubes) as well as the number and volume of the plasma samples must be accurately described. The laboratory techniques must be specific, sensitive, precise, reproducible, simple and robust. The two last specifications are important when large numbers of tests have to be performed in a short period and in several centres. Also the work capacity of each centre must be carefully evaluated and the admission rate adapted to it Disregarding the local situation will introduce unnecessary and easily avoidable technical and psychological difficulties. Quality and comparability of results obtained in different centms must be established and permanently controlled. The use of standards for each parameter is by far not sufficient Cooperative studies have repeatedly shown how difficult it is to obtain identical results sometimes to get values in the correct order for samples with undiscutably established activities or concentrations obtained by simple dilutions. Quality controls must be regularly performed starting before testing the study samples and during its entire
Fibrinolysis
duration. They must be organized to make internal quality in a centre totally independent of other centres. Thus others can not be made responsible for a centre own deficiency. A way of dealing with insufficient quality must be devised in advance. It is never an easy task. into consideration these Taking general recommendations one may expect to get better results, more significant correlations and aim to better practical applications. The final goals of epidemiological studies may widely vary: .
find out the best possible treatment for a well defined group of patients
.
elucidate physiopathological problems resulting in potentially more efficient type of treatment
.
find predictive tests for patients at risk leading to selective prophylactic measures
.
modify life style for disease prevention.
The final goal of all types of studies is in some way the prolongation of life. This does not go without possible adverse consequences. The medical community is frequently reluctant to accept clear cut results of predictive tests indicating that patients will no more have even the smallest benefit of
57
any active treatment. Furthermore, the problem of an aging popillation is very serious. Is it beneficial for the society at large to save at high costs some patients with coronary heart disease when sixty years old or older thus increasing the financial load supported by the young active and continuously relatively decreasing part of the population? It is nice to prevent arteriosclerosis by diet only and by reducing smoking. However, this could very well be the source of socioeconomic problems. For example it is convenient to recommend olive oil as a good source of fat in Italy. It goes hand in hand with Italian tradition and economy. It may cause problems in other countries were lard is readily available and olive oil not on the market and not produced by the farmers. In this respect the mass media may increase the beneficial effect of epidemiological studies, thoughtless use of irreproachable data may have harmful consequences. In certain circumstances, as for the beneficial influence of moderate wine consumption it may be preferable to keep the findings secret in order to avoid an exaggeration of alcoholism which is by itself sufficiently deleterious. Thus it is fair to recommend a pessimistic approach to epidemiological studies if one wants to smile at the very end of the study. These remarks do not pretend to be original. The fact is that they are too frequently forgotten.