Risk stratification in cardiovascular disease ... - Wiley Online Library

doi: 10.1111/j.1472-8206.2011.01023.x

Fundamental & Clinical Pharmacology

REVIEW ARTICLE

Risk stratification in cardiovascular disease primary prevention – scoring systems, novel markers, and imaging techniques Faiez Zannada*, Guy De Backerb, Ian Grahamc, Matthias Lorenzd, Giuseppe Manciae, David A. Morrowf, Zˇeljko Reinerg, Wolfgang Koenigh, Jean Dallongevillei, Robert J. Macfadyenj, Luis M. Ruilopek, Lars Wilhelmsenl, the ESC Working Group on CardioVascular Pharmacology and Drug Therapy a

Centre for Clinical Investigation, Institut Lorrain du Coeur et des Vaisseaux, CHU Brabois, 54500 Vandoeuvre, France Department of Public Health, Ghent University, De Pintelaan 185, Gent B-9000, Belgium c Department of Cardiology, Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland d Department of Neurology, Frankfurt University, Frankfurt D-60528, Germany e Division of Internal Medicine, University of Milan-Bicocca, Monza, Milan, Italy f Division of Cardiovascular Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA g University Hospital Center, School of Medicine, University of Zagreb, Salata 2, 10 000, Zagreb, Croatia h Department of Internal Medicine II Cardiology, University of Ulm Medical School, Robert-Koch Str 8, D-89081, Ulm, Germany i Department of Epidemiology and Public Health at Pasteur Institute of Lille, 1 rue du Pr. Calmette, BP 245, F-59019, Lille Cedex, France j University Department of Medicine, City Hospital, NHS Trust, Dudley Road, Birmingham B18 7QH, UK k Hypertension Unit, 12 de Octubre Hospital, Madrid 28041, Spain l Department of Medicine, University of Gothenburg, SE-405 30, Gothenburg, Sweden b

Keywords cardiovascular disease, carotid intima-media thickness, carotid plaques, C-reactive protein, primary prevention, risk stratification

Received 29 June 2011; revised 10 November 2011; accepted 2 December 2011

*Correspondence and reprints: [email protected]

ABSTRACT

The aim of this paper is to review and discuss current methods of risk stratification for cardiovascular disease (CVD) prevention, emerging biomarkers, and imaging techniques, and their relative merits and limitations. This report is based on discussions that took place among experts in the area during a special CardioVascular Clinical Trialists workshop organized by the European Society of Cardiology Working Group on Cardiovascular Pharmacology and Drug Therapy in September 2009. Classical risk factors such as blood pressure and low-density lipoprotein cholesterol levels remain the cornerstone of risk estimation in primary prevention but their use as a guide to management is limited by several factors: (i) thresholds for drug treatment vary with the available evidence for cost-effectiveness and benefit-to-risk ratios; (ii) assessment may be imprecise; (iii) residual risk may remain, even with effective control of dyslipidemia and hypertension. Novel measures include C-reactive protein, lipoprotein-associated phospholipase A2, genetic markers, and markers of subclinical organ damage, for which there are varying levels of evidence. Highresolution ultrasound and magnetic resonance imaging to assess carotid atherosclerotic lesions have potential but require further validation, standardization, and proof of clinical usefulness in the general population. In conclusion, classical risk scoring systems are available and inexpensive but have a number of limitations. Novel risk markers and imaging techniques may have a place in drug development and clinical trial design. However, their additional value above and beyond classical risk factors has yet to be determined for risk-guided therapy in CVD prevention.

ª 2012 The Authors Fundamental and Clinical Pharmacology ª 2012 Socie´te´ Franc¸aise de Pharmacologie et de The´rapeutique Fundamental & Clinical Pharmacology 26 (2012) 163–174

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INTRODUCTION To date, decisions regarding drug therapy for the prevention of cardiovascular disease (CVD) have relied on the assessment of classical risk factors to identify subjects who may be candidates for the initiation and optimization of therapy. Currently, drugs such as statins are mainly prescribed according to low-density lipoprotein cholesterol (LDL-C) level, antihypertensive drugs are prescribed according to blood pressure (BP) levels, and therapeutic targets are adjusted for additional risk (e.g., the presence of concomitant diabetes). The latest international guidelines have refined this approach by integrating total risk assessment for individual patients in therapeutic decision making [1–3]. The recent European Medicines Agency (EMEA) guideline on medicines for the prevention of CVD will allow drugs to be indicated on the basis of risk scores [4]. On the other hand, recent research has led to improved appreciation of pathophysiology that may be translated into improved diagnosis, prediction, prognostication, and risk subclassifications. Newer risk assessment tools may permit earlier and more targeted intervention. The present paper reviews currently available methods of risk stratification, as well as emerging biomarkers and imaging techniques. This is one of two reports based on the results of discussions that took place during a special CardioVascular Clinical Trialists (CVCT) workshop organized by the European Society of Cardiology (ESC) Working Group on Cardiovascular Pharmacology and Drug Therapy in September 2009. The manuscript has subsequently been reviewed and updated by all authors. The other report, ‘Prevention of CVD guided by total risk estimations – challenges and opportunities for practical implementation’, was published online in September 2011 [5]. DEVELOPMENTS IN CARDIOVASCULAR DISEASE RISK SCORING For many years, there has been a belief in cardiology that only half of the variance in CVD incidence can be explained through classical risk factors, including potentially modifiable factors such as smoking, diabetes, BP, and LDL-C levels, and two of the greatest (but nonmodifiable) risk predictors, age and sex [6]. In fact, most of the between-population and between-individual variance in CVD can be explained by classical risk factors. In the INTERHEART study, for example, nine potentially modifiable risk factors account for over 90% of the risk of experiencing an initial acute myocardial infarction (MI)

[7]. This association was present in men and women, old and young, and in all ethnic groups throughout the world. The Systematic COronary Risk Evaluation (SCORE) project was initiated by the ESC to develop a system of risk estimation for clinical practice in Europe [8]. The resulting risk stratification SCORE is based on a very large data set that is representative of European populations. Charts for high- and low-risk countries increase its applicability, and the chart can be recalibrated with local mortality data. Currently, SCORE is not applicable for people 70 years of age. However, a relative risk chart is available to show younger people with dyslipidemia or high BP that they are at increased lifetime risk for CVD, relative to others in their age group [3,9]. Such systems need to be simple if general physicians are to be encouraged to use them. Risk scoring systems need to improve the detection of young to middle-aged people with a low 10-year risk for CVD, but a moderate– high lifetime risk, so that they can benefit from early interventions such as lifestyle modification that aim to prevent progression to the high-risk group in later life. This is an area where newer assessments, such as inflammatory markers or carotid intima-media thickness (cIMT), might be used to reclassify people. The Reynolds Risk Score is a recently developed scoring system that incorporates a range of traditional and novel risk markers, and was shown to reclassify 40–50% of women at intermediate risk (according to ATP III prediction scores) into higher- or lower-risk categories [10]. The addition of high-sensitivity C-reactive protein (hsCRP) and parental history to the Reynolds Risk Score significantly improved cardiovascular risk prediction in men [11]. Using data from participants in the Framingham Heart Study, Lloyd-Jones and colleagues [12] estimated that the life-time risk of developing coronary heart disease (CHD) at age 40 in a general population was one in two for men and one in three for women. They suggested that this knowledge should promote efforts toward the detection and treatment of individuals at increased risk. The highest risk for CVD events is at the highest risk factor levels, which explains the intensive targeting of patients in this category – the ‘high-risk approach’. However, a large number of events occur in the many people at moderate risk, who may also benefit from preventive actions – the ‘population approach’. The importance of these two approaches, which are complementary, was emphasized by Rose [13]. The population strategy in preventive cardiology involves primarily community-oriented activities focusing on the whole


Novel markers in CVD risk stratification

population or subgroups. It is mainly concerned with health promotion, legislation, and primary prevention of the development of risk in the young [14]. That is, the aim is to ensure that healthy children preserve their ideal cardiovascular risk levels as they grow into adulthood. The high-risk concept mirrors the clinical approach to patients, and the scoring systems may indicate when to prescribe drugs. The intensity of the approaches should be adapted to the total cardiovascular risk of the subject. However, the cut-offs for drug treatment vary with the available evidence for risk-to-benefit ratios and costeffectiveness of drugs. In secondary prevention, as well as when end-organ damage is present, the CVD risk is elevated above that predicted based on the usual risk factors and drug treatment is generally valuable. Other potential limitations of classical risk factors include their use in isolation – the ‘single risk factor approach’. Separate guidelines on hypertension, diabetes, or dyslipidemias have this limitation; that is, they may mention other risk factors but the focus is on just one risk factor, which may be misleading. Nevertheless, basing treatment decisions on separate single risk factors such as initiating antihypertensive treatment based on BP and statins based on LDL-C levels has been shown to be effective. However, the assessment of classical risk factors may be imprecise. For example, characterizing a given subject by a single measurement of BP, LDL-C, or glucose levels, does not take into account either regression-dilution bias, biological variation over time or measurement errors. In most epidemiological cohort studies in the past, a risk factor was measured once at baseline, providing a single snapshot, and the cohort was then followed over time. However, lifelong exposure to most of the classical risk factors is not static but dynamic. As a result, risk scores based on single one-time measurement data may be inaccurate. Therefore, one should try to perform long-term studies with multiple measurements, and as precisely as possible, in order to achieve a clearer understanding of the true relationship between the risk factor and the incidence of CVD. Finally, no matter how well we control dyslipidemia and hypertension, residual risk remains in a proportion of patients because of the presence of other risk factors, some of which [e.g., low levels of high-density lipoprotein cholesterol (HDL-C)] may be modifiable with appropriate management [15]. Patients with the metabolic syndrome or diabetes are known to be at increased risk of early onset coronary artery disease (CAD). As a result, impaired fasting glucose (IFG) was incorporated in the American Heart Association/National Heart, Lung and

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Blood Institute definition of metabolic syndrome in 2005 [16]. The optimal glucose level has yet to be established, however, and hemoglobin A1c (HbA1c) may be a better measure of risk than IFG or impaired glucose tolerance. In individuals at high risk of diabetes but with normal glucose tolerance, a clear association has been demonstrated between elevated HbA1c (‡6.5%) and increased all-cause mortality [17]. In another recent study, non-diabetic hyperglycemia, assessed either by fasting glucose categories or continuously by HbA1c, was shown to correlate with both prevalence and severity of CAD [18]. Overall, one may conclude that the merits of the classical risk factors outweigh their limitations. The problem facing the implementation of CVD prevention is not the need for more personalized treatment but the failure to act in those with the potential to benefit. New clinical trial data would be required to support a SCOREguided new indication, which may limit opportunities to use older, generic drugs that are so far being prescribed based only on levels of individual risk factors. Many health insurance organizations will only reimburse statins and antihypertensive agents for patients with at least a 20% 10-year Framingham risk of CVD. As a result, people with a risk score 24% in 10 years for stroke, MI, or vascular death, irrespective of their FRS classification [72]. More recently, in the general population, the incremental predictive value of cIMT has been questioned based on results from the Carotid Atherosclerosis Progression Study (CAPS) [77]. After a 10-year followup of 4904 subjects without pre-existing vascular disease, cIMT was predictive for cardiovascular endpoints. However, compared with a model using the Framingham or the SCORE risk factors, a model that included the cIMT did not consistently improve the risk classification of individuals. Studies including larger numbers of subjects from other ethnic backgrounds are needed to demonstrate whether or not these results are generalizable to nonHispanic populations.

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For a general use of carotid ultrasound as a tool for risk classification and practical management of patients, more studies in the general population and in risk cohorts are needed with state-of-the-art statistics [78]. However, a meta-analysis of 41 trials found no relationship between cardiovascular drug-induced regression or slowed progression of cIMT and a reduction in cardiovascular events [79]. Another meta-analysis project (USE-cIMT, under the supervision of Michiel Bots, Erasmus Medical Center, Rotterdam, Netherlands) is underway to pool individual data from a series of large general-population cIMT studies. In summary, carotid ultrasound can identify target organ damage in patients with risk factors for atherosclerosis. Early detection of increased cIMT or plaque lesions and initiation of cardioprotective therapy may improve outcomes, but this needs to be investigated in prospective studies of asymptomatic patients at moderate risk for CVD. Carotid ultrasound may assist in the initial risk assessment of patients and in treatment decisions, but it is not yet appropriate for routine monitoring of patients during treatment. Coronary artery calcification score Coronary artery calcification (CAC) is a recognized characteristic of atherosclerosis. In 2000, an American College of Cardiology/American Heart Association consensus document assigned a Class IIb recommendation for the use of CAC assessment by cardiac computed tomography to improve cardiovascular risk assessment in intermediate-risk patients [80]. In a review of published prospective studies using non-invasive methods to detect subclinical atherosclerosis, Simon et al. [81] reported that both CAC and carotid plaque were ‘excellent’ for predicting CHD, while the other measures evaluated (cIMT, ankle-arm index and aortic pulse wave velocity) were only ‘fair’ (Table I) [81]. A more recent review of the evidence also confirmed that baseline CAC identifies coronary atherosclerosis, and that progression of CAC is associated with increased risk of cardiovascular events [82]. However, the authors noted that there is currently little evidence that any therapeutic interventions can slow the progression of CAC. They therefore suggested that quantification of CAC progression should not yet be recommended in routine clinical practice. The uncertainty surrounding the benefits or otherwise of CAC screening has been highlighted by two recent publications, one of which (a prospective randomized trial) found that CAC scanning was beneficial in terms of CAD risk factor control [83], and the other (a


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Table I Criteria for choosing subclinical atherosclerosis test. (Reprinted from Simon A et al. Comparative performance of subclinical atherosclerosis tests in predicting coronary heart disease in asymptomatic individuals. Eur. Heart J. (2007) 28 2967–2971 by permission of Oxford University Press [81].) Test criteria

cIMT

Ankle-arm index

Aortic PVW

Carotid plaque

Coronary calcium

Predictive value

Fair

Fair

Fair

Excellent

Excellent

Simplicity

Good

Excellent

Good

Good

Fair Fair

Reproducibility

Excellent

Fair

Fair

Good

Safety

Excellent

Excellent

Excellent

Excellent

Fair (radiation)

Low cost

Good

Excellent

Excellent

Good

Poor

cIMT, carotid intima-medica thickness; PWV, pulse wave velocity.

meta-analysis) reported limited evidence of benefit [84]. On the other hand, for clinical decision making, the association of CAC and event rates within conventional risk categories could be important to reclassify subjects appropriately. It may be used beneficially in intermediate-risk subjects, in whom the required intensity of therapy for risk factor modification is currently uncertain. In this category, a high CAC identifies subjects at high risk, in whom intensive treatment of risk factors may be warranted [85]. MAGNETIC RESONANCE IMAGING OF CAROTID ATHEROSCLEROTIC LESIONS In recent years, magnetic resonance (MR) imaging techniques have been developed to identify unstable, ‘vulnerable’ plaques. These techniques have shown good results in patho-histological validation studies, with reproducibility ranges between substantial and very good [86] where assessed. Clinical validation data are sparse [87,88] but promising. Before clinical application, however, standardization, assessment of reproducibility, proof of independent prediction of events and of clinical usefulness in terms of reclassification will be needed. MR imaging of carotid plaques is expensive and, while it may become useful to improve selection of subjects for carotid surgery or stenting, it is unlikely to be useful in the context of risk stratification in primary prevention. CORONARY MAGNETIC RESONANCE ANGIOGRAPHY Given the tremendous technical difficulties of displaying the coronary arteries with MR angiography with sufficient precision to classify coronary stenoses, the performance of contemporary MR techniques is impressive. However, the precision of these methods, validated against angiography, is limited: either sensitivity or specificity does not exceed 60–70% [89–91]. Given these limitations and the

cost of the investigation, there is still a long way to go before clinical utility in terms of risk stratification. CONCLUSIONS Current risk scoring systems for CVD prevention are available, inexpensive, and useful but may misclassify individuals with multiple and/or confounding factors. Most novel risk markers have yet to be evaluated in comparison with, and in the context of, classical risk factor scoring systems. Their role in risk-guided therapy for CVD prevention therefore remains uncertain. However, such markers may prove valuable for reclassification of risk in patients with non-classical risk factors. At present, one potential application for emerging biomarkers and imaging strategies is to guide drug development and clinical trial design. For example, trials could combine measurement of hsCRP to assess global risk and imaging to identify the extent of atherosclerotic disease. Such studies might be useful for assessing potential new therapies, adding evidence to support a go/no go decision, before a large commitment is made to execute a cardiovascular endpoint study. However, there is insufficient evidence to support biomarkers or imaging as primary endpoints for phase III evaluation of new drugs. Ongoing large studies, such as the BioIMAGE study (http:// www.clinicaltrials.gov NCT00738725), should provide additional information about the value of biomarkers and imaging techniques for risk assessment and treatment decisions. In the interim, we should aim to improve adherence to guidelines for the prevention of CVD, leading to better management of known risk factors. ACKNOWLEDGEMENTS The statements in the manuscript are based on the results of discussions that took place during a special CardioVascular Clinical Trialists workshop organized by



the European Society of Cardiology Working Group on CardioVascular Pharmacology and Drug Therapy in September 2009, with the following faculty: Christie Ballantyne (Houston), Pascale Benlian (Paris), Corine Bernaud (Brussels), Stefan Blankenberg (Mainz), Jan Buch (Copenhagen), Alberico Catapano (Milan), Renata Cifkova (Prague), Jean Dallongeville (Lille), Guy De Backer (Ghent), Ian Graham (Dublin), Javier Jimenez (Brussels), Wolfgang Koenig (Ulm), Matthias Lorenz (Frankfurt/Main), Robert MacFadyen (Birmingham), Giuseppe Mancia (Milan), David Morrow (Boston), Gunnar Olsson (Mo¨lndal), Krishna Prasad (London), Zeljko Reiner (Zagreb), James Revkin (Ridgefiled), Edmond Roland (Paris), Luis Ruilope (Madrid), Pierrre-Jean Touboul (Paris), Lars Wilhelmsen (Gothenburg), Faiez Zannad (Chairman, Nancy). FUNDING This workshop was supported by an unrestricted medical education grant from AstraZeneca. The initial drafts of the manuscript were written by the authors. We thank Liz Anfield from Prime Medica Ltd, Knutsford, Cheshire, who provided medical writing assistance funded by AstraZeneca. Employees of AstraZeneca were permitted to read the manuscript at a late stage in its development. Responsibility for opinions, conclusions, and interpretation of the data lies with the authors. CONFLICT OF INTEREST Jean Dallongeville received research grants from AstraZeneca, Sanofi-Aventis, and Pfizer; and consultant/ speaker for AstraZeneca, MSD, Sanofi-Aventis, Novartis and Danone. Guy De Backer has received honoraria as a speaker from AstraZeneca. Ian Graham received speaker fees and unrestricted educational grants from Pfizer and MSD. Wolfgang Koenig received research support grants from Mercodia, Roche and Brahms; lecture fees from AstraZeneca, Merck, Sharp & Dohme, GlaxoSmithKline, diaDexus, and Boehringer-Ingelheim; and consulting fees from GlaxoSmithKline and Roche. Dr Koenig is a member of the Steering Committee of the JUPITER trial. Matthias Lorenz, Robert J. Macfadyen, Giuseppe Mancia, Giuseppe Mancia, Luis M Ruilope, and Lars Wilhelmsen declare no conflict of interest. David A. Morrow is the consultant for Beckman Coulter, Boehringer Ingelheim, Gilead, Instrumentation Laboratory, Menarini, OrthoClinical Diagnostics, Roche Diagnostics, Sanofi-Aventis, Schering Plough, and Siemens; remuneration for serving

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on a Clinical Events Committee from AstraZeneca; research grant support to Brigham & Women’s hospital from AstraZeneca, Bayer Healthcare, Beckman Coulter, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly and Co, GlaxoSmithKline, Merck and Company, Nanosphere, Novartis Pharmaceuticals, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, Sanofi-Aventis, Siemens, and Singulex. Zˇeljko Reiner received honoraria as a speaker from Solvay, MSD, Pfizer, and AstraZeneca. Faiez Zannad received consultant honoraria and/or lecture fees from Servier; AstraZeneca, Pfizer, Boehringer Ingelheim, Novartis, Abbott, Relypsa, Resmed, Merck, Daiichi Sankyo, Takeda, Boston Scientific; Medtronic, and Otsuka. REFERENCES 1 Mancia G., De Backer G., Dominiczak A. et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J. Hypertens. (2007) 25 1105–1187. 2 Mancia G., Laurent S., Agabiti-Rosei E. et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J. Hypertens. (2009) 27 2121–2158. 3 Graham I., Atar D., Borch-Johnsen K. et al. European guidelines on cardiovascular disease prevention in clinical practice: full text. Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Eur. J. Cardiovasc. Prev. Rehabil. (2007) 14(Suppl 2) S1–S113. 4 European Medicines Agency. Guideline on the evaluation of medicinal products for cardiovascular disease prevention. London: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/ WC500003290.pdf [accessed on 2010 July 19]. 5 Zannad F., Dallongeville J., Macfadyen R.J. et al. Prevention of cardiovascular disease guided by total risk estimation – challenges and opportunities for practical implementation: highlights of a CardioVascular Clinical Trialists (CVCT) Workshop of the ESC Working Group on CardioVascular Pharmacology and Drug Therapy. Eur. J. Cardiovasc. Prev. Rehabil. (2011) (epub ahead of print). 6 Cooney M.T., Dudina A.L., Graham I.M. Value and limitations of existing scores for the assessment of cardiovascular risk. A review for clinicians. J. Am. Coll. Cardiol. (2009) 54 1209–1227. 7 Yusuf S., Hawken S., Ounpuu S. et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet (2004) 364 937–952. 8 Conroy R.M., Pyorala K., Fitzgerald A.P. et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur. Heart J. (2003) 24 987–1003.


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