(Circulation. 1997;96:2449-2452.)
© 1997 American Heart Association, Inc.
Articles |
Coronary Risk Estimation and Treatment of Hypercholesterolemia
From the Centre de Médecine Préventive Cardiovasculaire, CR Inserm, Hôpital Broussais, Paris, France.
 |
Abstract |
|---|
 Top Abstract IntroductionPrinciples of Rational Decision...Application of Rational...Limitations and Hazards of...Proposals for Risk-Based...References |
|---|
Background Evidence-based treatment of hypercholesterolemia currently recommended for rationalizing drug prescription requires justification of treatment by randomized trials, such as the West of Scotland Coronary Prevention Study (WOSCOPS) or the Scandinavian Simvastatin Survival Study (4S), and evaluation of its benefit from the estimation of the coronary risk of each patient.
Methods and Results The latest European guidelines and Sheffield tables apply these principles and justify the decision to treat hypercholesterolemia if the Framingham coronary multivariate risk estimate is high enough, ie, >20% risk of coronary event at 10 years in the former and >1.5% risk of coronary death per year in the latter. Nevertheless, the practice of these two recent guidelines results in discrepancies in the decision to treat, because coronary morbidity was considered in one but mortality was considered in the other, and the risk required for treating may be extrapolated from different trials (4S or WOSCOPS).
Conclusions Although the principle of targeting lipid-lowering treatment to high-risk subjects is unquestioned, further studies are needed to demonstrate that the Framingham risk profile is useful in selecting persons who are likely to benefit and to determine the place of newer risk factors and that of early noninvasive detection of atheroma in the risk estimation–based treatment.
Key Words: atherosclerosis • hypercholesterolemia • lipids • risk factors
|
Introduction |
|---|
|
TopAbstractIntroductionPrinciples of Rational Decision...Application of Rational...Limitations and Hazards of...Proposals for Risk-Based...References |
|---|
The uncertainties in medical practice resulting from biological variability have implications for quality and cost of health care.1 A possible solution is provided by the concept of evidence-based medical management characterized by two fundamental principles2 3 : justification of the clinical decision by the best available scientific information and evaluation in each patient of the benefit of an intervention by estimating his or her baseline risk before the clinical decision. Because this concept is currently proposed for rationalizing lipid-lowering drug treatment for prevention of coronary disease,3 4 5 we will discuss its possibilities and limitations, with special attention to the potential usefulness of improving the coronary risk estimate in asymptomatic individuals by use of noninvasive techniques to identify early atheroma.
|
Principles of Rational Decision for Treatment in Hypercholesterolemia |
|---|
|
TopAbstractIntroductionPrinciples of Rational Decision...Application of Rational...Limitations and Hazards of...Proposals for Risk-Based...References |
|---|
The two key steps in rational therapeutic decision making in hypercholesterolemia are as follows. First, the decision to treat must be based on the results of randomized lipid-lowering drug trials.4 6 Second, the individual benefit of treating a subject must be evaluated on the basis of his or her pretreatment coronary risk.3 The decision to treat hypercholesterolemia pharmacologically is justified by the reduction in coronary morbidity and mortality demonstrated with active drug treatment compared with placebo in several trials.7 8 9 10 11 12 13 In primary prevention, the latest West of Scotland Coronary Prevention Study (WOSCOPS) has shown a relative risk reduction under pravastatin treatment of 29% (95% CI, 15% to 40%) for coronary events and 33% (1% to 55%) for coronary deaths11 (Table 1
). The WOSCOPS also indicated that
active treatment reduced all-cause mortality almost significantly, by
22% (0% to 40%) (Table 1).11 In secondary prevention,
the Scandinavian Simvastatin Survival Study (4S) has shown
that simvastatin treatment reduced coronary
morbidity by 34% (25% to 41%), coronary mortality by 42%
(27% to 54%), and all-cause mortality by 30% (15% to
42%)13 (Table 1). The individual benefit of
cholesterol treatment, expressed in terms of absolute
reduction in coronary risk, can be calculated in each subject
as the product between the relative coronary risk reduction
reported in a trial and his or her pretreatment coronary risk
estimate. Such a calculation assumes that the relative risk reduction
is constant for all levels of risk. Taking the 30% relative risk
reduction in coronary morbidity reported in WOSCOPS, the
absolute risk reduction expected from cholesterol treatment
in a subject with a pretreatment coronary 5-year risk of 5%
will be 1.5%, and that in a subject with a pretreatment
coronary 5-year risk of 20% will be 6%. This example shows
that the benefit to treat one individual is directly related to the
pretreatment absolute risk.14
|
|
Application of Rational Treatment of Cholesterol in Clinical Practice |
|---|
|
TopAbstractIntroductionPrinciples of Rational Decision...Application of Rational...Limitations and Hazards of...Proposals for Risk-Based...References |
|---|
In clinical medicine, doctors should therefore estimate the pretreatment coronary risk of each patient and know whether this risk is sufficiently high to obtain a benefit from treatment. Accordingly, the latest European guidelines have recommended calculation of the patient's 10-year risk of a coronary event with a table based on the Framingham risk functions.14 If diet fails, subjects with moderate cholesterol elevation and a coronary 10-year risk >20% are candidates for drug treatment.14 In practice, any male smoker
50 years old
or female smoker 60 years old with a cholesterol level
from 7 to 8 mmol/L falls into this category. Other, more
conservative guidelines have been based on tables (the Sheffield
tables) showing the minimum rise in cholesterol required
before one reaches a coronary risk that justifies
pravastatin treatment according to the presence or absence
of coexisting risk factors.15 The risk in these tables was
that of coronary death in the 4S (1.5% per
year),13 calculated with the Framingham risk
functions.16 The Sheffield tables indicate that in men or
women free of risk factors other than
hypercholesterolemia, cholesterol
treatment is not justified at any age and at any realistic
cholesterol concentration up to 9 mmol/L. They
also show that even in the presence of two major risk factors
(hypertension and smoking), moderate
hypercholesterolemia <8 mmol/L
does not justify drug treatment in men <65 years old or in women at
any age. |
Limitations and Hazards of Rational Cholesterol Treatment |
|---|
|
TopAbstractIntroductionPrinciples of Rational Decision...Application of Rational...Limitations and Hazards of...Proposals for Risk-Based...References |
|---|
Rational decision on lipid-lowering drug treatment on the basis of coronary risk estimation raises several important issues that have not yet been solved.
A first issue concerns the targeting of absolute initial
coronary risk required for obtaining a benefit from treatment.
Estimates of that potential benefit used in the above-mentioned
guidelines and tables are inconsistent, because these
guidelines and tables have at times considered mortality (Sheffield
tables) and at other times morbidity (European guidelines), and the
risk required for treatment may be extrapolated from different
trials.17 Great differences in the decision to treat arise
between the two guidelines, because the decision to treat
cholesterol pharmacologically will concern a much greater
number of subjects if the European guidelines are used than the
Sheffield tables (Table 2). This
discrepancy may be misleading and introduce a major element of
confusion for the clinician. A second important issue is that no trial,
to the best of our knowledge, has ever demonstrated that the Framingham
coronary risk profile is useful in selecting persons who are
likely to benefit from lowering of the lipid profile. A corollary
concern is that even though correction of dyslipidemia has
demonstrated a significant and substantial benefit for preventing both
initial and recurrent fatal and nonfatal events, a reliable estimate of
that benefit is not available, in particular with regard to the
treatment according to type of dyslipidemia present,
and overall with regard to whether other risk factors are present.
A final issue concerns the accuracy of the Framingham
multivariate risk in reflecting the true overall
coronary risk in one individual, because the Framingham risk
estimation takes into account only some traditional risk
factors.16 Moreover, although the Framingham risk profile
has been found to be reasonably accurate in numerous countries, such as
western Europe, Australia, and New Zealand, it is not accurate for
absolute risk in low-risk populations such as southern Europe, Asia,
and Latin America, where it tends to overestimate risk.18
Furthermore, the Framingham risk estimate is not a discrete number but
rather an average with 95% CIs,16 which implies that the
decision to treat would be based on a range of risk rather than on a
single value. Finally, there is no agreement as to whether the
Framingham assessment of risk should be made over a lifetime, over a
5-year period, or over 10 years. Various guidelines and tables have
used different criteria here. Perhaps one can manipulate the results
depending on one's point of view. It is not certain that the same
criteria and the same periods of review should be used in primary
prevention and in secondary prevention.
|
|
Proposals for Risk-Based Treatment of Hypercholesterolemia |
|---|
|
TopAbstractIntroductionPrinciples of Rational Decision...Application of Rational...Limitations and Hazards of...Proposals for Risk-Based...References |
|---|
Because the absolute benefit to be expected from lipid-lowering treatment depends on the level of coronary risk, the importance of targeting treatment to hypercholesterolemic subjects at higher risk is unquestionable.14 Nevertheless, a number of above-mentioned issues should be resolved before such a target is implemented in clinical practice.
First, an agreement must be found between various guidelines and tables to define the type of coronary risk, death or event, and the threshold of risk required for treating. It seems logical to consider morbidity rather than mortality, because one should be concerned not only about fatal events but also about nonfatal infarction, angina, cardiac failure, the resulting reductions in life expectation and quality of life, and the medical and social costs. Furthermore, the risk required for treatment in primary prevention should be extrapolated from primary prevention trials, because the mechanisms that govern recurrent complications in established coronary disease are probably not similar to those involved in the preclinical stage.17 19
Second, a definitive demonstration that the Framingham coronary risk profile is useful in selecting persons who are likely to benefit from lipid-lowering treatment would require a trial in which lipid-lowering drug treatment is implemented on the basis of multivariate risk and morbidity and mortality outcomes examined compared with treatment assigned on the basis of lipid values alone.
Third, because the Framingham risk profile does not take into account all known risk factors,16 there are certainly other risk factors that might be important in considering the urgency for treatment. Established risk factors for cardiovascular disease, such as heredity, lack of physical exercise, and body weight,20 21 need to be considered in planning treatment but do not greatly improve the risk estimation because they are largely mediated by the variables in the Framingham profile,16 18 and the first two factors are difficult to assess accurately. In contrast, newer risk markers, such as fibrinogen, plasminogen activator inhibitors, lipoprotein (a), homocysteine, insulin resistance, and small dense LDL cholesterol, might be important to consider and add to the multivariate risk profile when there is sufficient epidemiological evidence to allow a reliable estimation of their independent contribution to risk.22 This latter point has been demonstrated for plasma fibrinogen, whose dosage could therefore improve the risk estimation.23
In other respects, the fact that the Framingham risk profile may overestimate the absolute coronary risk in a low-risk population may be overcome by an appropriate change of the intercept in the Framingham model, as recently demonstrated in a French working population.24 In addition, even in a low-risk population, the Framingham risk profile provides an estimate of relative risk and can distinguish high- from low-risk persons in such populations.
Last but not least, the coronary risk estimation might be greatly improved by the noninvasive detection of early atheroma formation,25 such as plaque at multiple extracoronary sites26 or carotid/femoral intima-media thickening27 28 accurately assessed by ultrasonography. Preclinical atheroma will undoubtedly identify persons at increased risk of coronary events because it is the consequence of time-integrated exposure to multiple risk factors, known or unknown, and therefore offers a reflection of the global multifactorial risk.29 30 Some studies have shown that early atheroma, especially in carotid arteries, is probably a powerful indicator and predictor of coronary artery disease.26 27 31 Moreover, it is well known that many events arise out of nonocclusive-appearing lesions that fissure and undergo subintimal hemorrhage, but factors that cause these phenomena are probably different from those that influence the progression of atherosclerosis.19 Nevertheless, even if several studies have shown that lipid-lowering drug treatment retarded the rate of progression of ultrasonographically assessed carotid atheroma parallel to a reduction in incident coronary events,32 trial data on the benefit of treatment based on noninvasive arterial disease assessment are needed. Furthermore, the cost implications of moving to noninvasive arterial assessment before preventive measures have been tried must be taken into account. Such assessment would preferentially be done on individuals borderline for lipid-lowering drug treatment and not for all hypercholesterolemic patients. The bulk of coronary events arise from this segment of the population, but this subgroup also constitutes a huge segment of the general population.22 Because a substantial proportion of subjects borderline for treatment are free of preclinical atheroma and could be therefore managed without drugs,25 important savings might be made. Indeed, the cost of noninvasive echographic arterial assessment represents the cost of only a few months of treatment with an HMG-CoA reductase inhibitor.25
In conclusion, a large amount of work needs to be done before we can
recommend basing the decision for treating
hypercholesterolemia on the coronary
risk estimation (Table 3). Meanwhile,
family practitioners should be encouraged to estimate more
extensively the multifactorial coronary risk profile in
hypercholesterolemic subjects. Indeed, the Framingham
multivariate risk estimation is efficient and feasible
because it involves only ordinary office procedures and simple
laboratory tests and can target persons who should receive treatment
and eliminate those who would have little to gain. Optimally, subjects
found by multivariate risk estimation to be borderline
for therapy might be referred, before a final therapeutic decision, to
centers for primary patient care to undergo a complementary risk
evaluation, including biological testing of newer risk markers and
low-cost, noninvasive assessment of early atheroma
formation.
|
|
Acknowledgments |
|---|
We thank Isabelle d'Argentré for her invaluable secretarial assistance in preparing the manuscript.
|
Footnotes |
|---|
Reprint requests to Professeur Alain Simon, Centre de Médecine Préventive Cardiovasculaire, 96 rue Didot, 75674 Paris Cedex 14, France.
|
References |
|---|
|
TopAbstractIntroductionPrinciples of Rational Decision...Application of Rational...Limitations and Hazards of...Proposals for Risk-Based...References |
|---|
1. Logan RL, Scott PJ. Uncertainty in clinical practice: implications for quality and costs of health care. Lancet. 1996;347:595-598.[Medline] [Order article via Infotrieve]
2. Linberg DA. Information systems to support medical practice and scientific discovery. Methods Inf Med. 1989;28:202-206.[Medline] [Order article via Infotrieve]
3. Jackson R, Beaglehole R. Evidence-based management of dyslipidaemia. Lancet. 1995;346:1140-1142.
4.
Bucher HC, Weinbacker M, Gyr K. Influence of
method of reporting study results on decision of physicians to
prescribe drugs to lower cholesterol concentration.
BMJ. 1994;309:761-764.
5. Smith GD, Pekkanen J. Should there be a moratorium on the use of cholesterol lowering drugs? BMJ. 1992;304:431-434.
6. Brett AS. Treating hypercholesterolemia: how should practicing physicians interpret the published data for patients? N Engl J Med. 1989;321:676-680.[Medline] [Order article via Infotrieve]
7.
A co-operative trial in the primary prevention of
ischaemic heart disease using cloribrate: report from the Committee of
Principal Investigators. Br Heart J. 1978;40:1069-1118.
8.
The Lipid Research Clinics Coronary Primary
Prevention Trial results, I: reduction in incidence of coronary
heart disease. JAMA. 1984;251:351-364.
9.
The Lipid Research Clinics Coronary Primary
Prevention Trial results, II: the relationship of reduction in
incidence of coronary heart disease to cholesterol
lowering. JAMA. 1984;251:365-374.
10. Frick MH, Elo OE, Haapa KK, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Mäenpää H, Mälkönen M, Mänttäri P, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjöblom T, Nikkilä EA. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237-1245.[Abstract]
11.
Shepherd J, Cobbe SM, Ford I, Isles C, Lorimer AR,
Macfarlane W, McKillop J, Packard CJ, for the West of Scotland
Coronary Prevention Study Group. Prevention of coronary
heart disease with pravastatin in men with
hypercholesterolemia. N Engl J
Med. 1995;333:1301-1307.
12.
LaRosa JC, Cleeman JI. Cholesterol
lowering as a treatment for established coronary heart
disease. Circulation. 1992;85:1229-1235.
13. Scandinavian Simvastatin Survival Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.[Medline] [Order article via Infotrieve]
14.
Pyörälä K, De Backer G, Graham I,
Poole-Wilson P, Wood D, on behalf of the Task Force. Prevention of
coronary heart disease in clinical practice: recommendations of
the Task Force of the European Society of Cardiology,
European Atherosclerosis Society and European Society
of Hypertension. Eur Heart J. 1994;15:1300-1331.
15. Haq IU, Jackson PR, Yeo WW, Ramsay LE. Sheffield risk and treatment table for cholesterol lowering for primary prevention of coronary heart disease. Lancet. 1995;366:1467-1471.
16. Anderson KM, Odell PM, Wilson PWF, Kannel WB. Cardiovascular disease risk profiles. Am Heart J. 1991;121:293-298.[Medline] [Order article via Infotrieve]
17. Megnien JL, Levenson J, Simon A. Sheffield risk and treatment table for cholesterol lowering in prevention of coronary heart disease. Lancet. 1996;347:468. Letter.[Medline] [Order article via Infotrieve]
18. Gordon T, Kannel WB. Multiple risk functions for predicting coronary heart disease: the concept, accuracy and application. Am Heart J. 1982;103:1031-1039.[Medline] [Order article via Infotrieve]
19. Badimon JJ, Fuster V, Chesebro JH, Badimon L. Coronary atherosclerosis: a multifactorial disease. Circulation. 1993;87(suppl II):II-3-II-16.
20.
Berlin JA, Colditz Ga. A meta-analysis of
physical activity in the prevention of coronary heart disease.
Am J Epidemiol. 1990;132:612-628.
21. Larsson B. Obesity and body fat distribution as predictors of coronary heart disease. In: Marmot M, Elliot P, eds. Coronary Heart Disease Epidemiology: From Aetiology to Public Health. Oxford, UK; Oxford University Press; 1992:233-241.
22. Castelli WP. Lipids, risk factors and ischaemic heart disease. Atherosclerosis. 1996;124:S1-S9.
23.
Ernst E, Resch KL. Fibrinogen as a
cardiovascular risk factor: a meta-analysis and
review of the literature. Ann Intern Med. 1993;118:956-963.
24. Laurier D, Chau NP, Cazelles B, Segond P, PCV METRA Group. Estimation of CHD risk in a French working population using a modified Framingham model. J Clin Epidemiol. 1994;47:1353-1364.[Medline] [Order article via Infotrieve]
25. Simon A, Levenson J. Could the identification of subclinical atherosclerosis offer an alternative to the mass drug treatment of hypercholesterolemia? Atherosclerosis. 1994;105:245-249.[Medline] [Order article via Infotrieve]
26.
Simon A, Giral P, Levenson J.
Extracoronary atherosclerotic plaque at multiples sites and
total coronary calcification deposit in
asymptomatic men. Circulation. 1995;92:1414-1421.
27.
Crouse JR, Craven TE, Hagaman AP, Bond MG.
Association of coronary disease with segment-specific
intimal-medial thickening of the extracranial carotid artery.
Circulation. 1995;92:1141-1147.
28. Gariepy J, Simon A, Massonneau M, Linhart A, Levenson J, PCV METRA Group. Wall thickening of carotid and femoral arteries in male subjects with isolated hypercholesterolemia. Atherosclerosis. 1995;113:141-151.[Medline] [Order article via Infotrieve]
29.
Devereux RB, Alderman MH. Role of preclinical
cardiovascular disease in the evolution from risk
factor exposure to development of morbid events.
Circulation. 1993;88:1444-1455.
30.
Levenson J, Giral P, Razavian M, Gariepy J, Simon
A. Fibrinogen and silent atherosclerosis in
subjects with cardiovascular risk factors.
Arterioscler Thromb Vasc Biol. 1995;15:1263-1268.
31.
Salonen JT, Salonen R. Ultrasonographically
assessed carotid morphology and the risk of coronary heart
disease. Arterioscler Thromb. 1991;11:1245-1249.
32.
Blankenhorn DH, Hodis HN. Arterial
imaging and atherosclerosis reversal.
Arterioscler Thromb. 1994;14:177-192.
This article has been cited by other articles:
 |
|
 |
|
  G. Chironi, A. Simon, B. Hugel, M. Del Pino, J. Gariepy, J.-M. Freyssinet, and A. Tedgui Circulating Leukocyte-Derived Microparticles Predict Subclinical Atherosclerosis Burden in Asymptomatic Subjects Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2775 - 2780. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Poredos Intima-media thickness: indicator of cardiovascular risk and measure of the extent of atherosclerosis Vascular Medicine, February 1, 2004; 9(1): 46 - 54. [Abstract] [PDF]
|
|
|
|
 |
|
 R. Scalia, M. E. Gooszen, S. P. Jones, M. Hoffmeyer, D. M. Rimmer III, S. D. Trocha, P. L. Huang, M. B. Smith, A. M. Lefer, and D. J. Lefer Simvastatin Exerts Both Anti-inflammatory and Cardioprotective Effects in Apolipoprotein E-Deficient Mice Circulation, May 29, 2001; 103(21): 2598 - 2603. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Papoz, A. Ponton, P. Segond, F. Becker, L. Drouet, J. Levenson, M. Marazanof, Y. Sentou, E. Chollet, J. Etiemble, et al. Feasibility and Reliability of Ankle/Arm Blood Pressure Index in Preventive Medicine Angiology, June 1, 2000; 51(6): 463 - 471. [Abstract] [PDF]
|
|
|
|
|
|
P. Greenland, S. Grundy, R. C. Pasternak, and C. Lenfant Problems on the Pathway From Risk Assessment to Risk Reduction Circulation, May 19, 1998; 97(18): 1761 - 1762. [Full Text] [PDF]
|
|
|
|
|
|
J. Gariepy, J. Salomon, N. Denarie, F. Laskri, J. L. Megnien, J. Levenson, and A. Simon Sex and Topographic Differences in Associations Between Large-Artery Wall Thickness and Coronary Risk Profile in a French Working Cohort : The AXA Study Arterioscler Thromb Vasc Biol, April 1, 1998; 18(4): 584 - 590. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||