New biomarkers, with the potential to serve as indicators of cardiovascular risk, are continually emerging. The validity of several of these was examined by this round table Group, who assessed the merits of biomarkers as additions or replacements to those markers currently in clinical use.
Estimated glomerular filtration rate (eGFR)
Reporting of eGFR started in April 2006, having been advocated in Part 2 of the National Service Framework for Renal Services.1 Testing for this biomarker has a dual function. It helps to identify patients with impaired chronic renal dysfunction at an early stage and, more importantly, it is proving to be a strong marker of adverse cardiovascular (CV) outcomes. Several databases, e.g. the Kaiser Permanente patient registry, show a clear gradient of increased CV risk in parallel with deteriorating renal function as measured by eGFR.2 The Reykjavik study3 suggests there is an eGFR threshold of 60 ml/min/1.73 m2, below which the risk of CV events increases independently of other risk factors. A very low eGFR suggests the risk of CV death may be increased by as much as 40%, independent of other CV risk factors, such as advanced age, dyslipidaemia and raised blood pressure.3
Age correction is important when interpreting whether a result is normal. Renal function is stable up until age 40, but thereafter 0.7 to 0.9 ml/min is lost per year in the normal (healthy) population. By age 80, the prevalence of an eGFR of 60 ml/min/1.73 m2 or less may be greater than 70%.4 Nevertheless, a low eGFR is still associated with increased CV risk, probably indicating subclinical atherosclerosis.
The group acknowledged that testing eGFR is a procedure for outpatient or primary care settings, whereas in acute settings creatinine is a more useful indicator of impaired renal function.
Low eGFR: to treat or not to treat
There is confusion currently about whether to treat a low eGFR in the absence of other uncontrolled risk factors and whether traditional treatments, such as statins, used in cardiovascular prevention can reverse renal impairment. Nephrologists advise that patients with a low eGFR should not be referred to a renal specialist unless proteinuria is present but angiotensin-converting enzyme (ACE) inhibitors can be started before this point.
‘Brain-type natriuretic peptide (BNP) is primarily a marker of cardiac mortality’
A declining eGFR in younger patients (<70 years) can indicate that a more aggressive approach to CV risk factor management is needed. There is little evidence to support this, but most clinical trials of statins have excluded patients with signs of renal dysfunction. A retrospective meta-analysis of more than 19,000 patients with impaired renal function, who received either pravastatin or placebo, did suggest a benefit from a statin. The analysis included outcomes among patients who had normal kidney function at entry but could be categorised into high, medium or low normal values. Receiving a statin had a beneficial impact on outcomes among those with high normal creatinine values, with approximately 6% absolute risk reduction for CV events.5
Risk factor interventions are less likely to be helpful in patients with advanced kidney disease or among those receiving dialysis, the Group maintained, since their pathology involves arterial calcification and stiffness rather than lipid-related problems. It is not known whether lipid-lowering therapy has any impact on renal function and risk reduction in this group, and in any case diabetic patients with advanced renal disease are likely to be already undergoing aggressive treatment with risk-factor modifying medications.
The Group concluded that plentiful data support use of eGFR as a marker for identifying individuals at high risk of CVD and that it could add value to risk scoring systems. The absence of clinical trial data means the Group were uncertain of the value of including a population-screening tool that has no evidence base for changing management. GPs, they felt, would be better advised to screen patients for proteinuria and to aim to lower blood pressure to a target of 125/75 mmHg when this is found. Routine screening for microalbuminuria is currently
High-density lipoprotein (HDL) cholesterol
Low levels of HDL cholesterol (below 1.0 mmol/L) are well recognised to be a cardiovascular disease risk factor and the Group debated whether there should be wider screening for this. Levels are not routinely measured currently (except in diabetes) as there have been few well-tolerated interventions. Full lipid analyses of low-density lipoprotein (LDL) cholesterol, HDL cholesterol and triglycerides should be carried out in patients with diabetes, however, as low HDL-C levels are common in this group.
Specific HDL cholesterol treatment targets are not recommended in National Institute for Health and Clinical Excellence (NICE) or Joint British Societies’ (JBS 2) guidelines6,7 although a European consensus panel advocated a minimum target of 1.03 mmol/L in patients with coronary heart disease (CHD) or a high level of CHD risk.8
Most statins will raise HDL cholesterol slightly (approximately 0.05 – 0.1 mmol/L) but the Group believed that this only had a small impact on outcomes. Lifestyle interventions, such as smoking cessation, exercise and weight loss, will improve HDL cholesterol by around 5 to 10%, while fibrates and nicotinic acid will raise levels by 5 to 15%, and 15 to 30%, respectively.9
‘Routine measurement of high-sensitivity C-reactive protein (hs-CRP) is inadvisable, except in acute care settings’
The NICE lipid modification clinical guideline states that nicotinic acid should not be offered for the primary prevention of CVD. It may be considered for secondary prevention in people with CVD who are not able to tolerate statins.6 The NICE type 2 diabetes clinical guideline gives no general recommendation on the use of nicotinic acid in people with type 2 diabetes due to limited outcome trials in patients of this type.10
The Group recommended that patients with low HDL cholesterol levels should be managed to increase these to a target of 1.0 mmol/L since epidemiological data have shown an increased risk of CV mortality for levels below this.8 An early trial of nicotinic acid demonstrated that intervention reduced CV events, but some Group members felt that hard prospective clinical trial outcome data were needed.
Raising HDL cholesterol is more difficult in elderly patients due to the side effects of current drugs. An alternative strategy is to lower LDL cholesterol aggressively to provide greater gains in absolute risk reduction, although there were concerns about this approach due to a lack of data for women and older people in primary prevention.
Lifestyle intervention, including weight reduction, smoking cessation and increasing exercise, should be recommended for individuals with low levels of HDL cholesterol.
High-sensitivity C-reactive protein (hs-CRP)
The biomarker hs-CRP is not available for measurement routinely in most clinical laboratories but it is gaining credibility in the research community from epidemiological studies as an emerging marker of increased CV risk.11 Hs-CRP values show a gradient of relative risk,12 with increased risk linked to CHD death and non-fatal myocardial infarction (MI).
Many factors can raise hs-CRP values (table 1). Hs-CRP values are also raised when LDL cholesterol or triglycerides are high and when HDL is low, but offer independent risk prediction to these variables.13
Statins consistently lower hs-CRP and some analyses suggest that this ‘on-treatment’ hs-CRP lowering predicts benefit, but an outcomes benefit is difficult to show due to the many causes of raised hs-CRP. Furthermore current hs-CRP-lowering treatments have other effects and any causal role of hs-CRP will need to be established by outcome trials of specific hs-CRP inhibitors.
‘It is debatable whether apolipoproteins can aid clinical decision-making’
The Group were uncertain whether hs-CRP plays a causal role in increasing CV risk or is merely a marker of other pathological processes in progress. No European or British recommendations give advice on hs-CRP but a consensus statement of the American Heart Association and Centers for Disease Control and Prevention recommends considering using hs-CRP to screen patients with intermediate CV risk (10–20% by Framingham calculation over 10 years) on a population basis using a cutpoint of hs-CRP >3 mg/L to identify high-risk groups.14 Hs-CRP is more closely associated with stroke than LDL cholesterol so, theoretically, lowering hs-CRP with statins or by other means would benefit patients at increased risk of stroke.15
Measuring hs-CRP routinely, other than in acute care settings, was considered currently inadvisable by the Group. Factoring hs-CRP into computer risk algorithms could potentially enable up to 50% of intermediate-risk patients to be reclassified correctly as being in a higher or lower risk category group.16 Better classification and appropriate intervention adjustment has tremendous potential for generating cost savings. High-sensitivity CRP measurement would only be useful for patients not identified as being at increased CV risk by other means.
The Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial was designed to assess the effectiveness of a statin in the primary prevention of cardiovascular events in individuals with normal LDL-C and elevated hs-CRP.17 The results of this are awaited. Many interventions lower hs-CRP, including lifestyle changes, such as exercise and Mediterranean diet, blood pressure reduction, establishing good glycaemic control and glitazones.
The Group was divided as to whether they would consider using a more powerful statin or adding ezetimibe to a statin to treat the lipids of patients with high hs-CRP readings more aggressively. Outcome data are needed to justify the strategy.
Other biomarkers of CV risk
Other biomarkers of CV risk include apolipoproteins, brain-type natriuretic peptide (BNP) and troponin. Their merits relative to other biomarkers of risk, such as LDL and HDL cholesterol, are summarised in table 218–21
Q: What about the use of isoprostane?
A: This is a promising early biomarker of CV risk from oxidative stress and endothelial dysfunction, although assays are probably not robust.
- The National Service Framework for Renal Services. Part 2: Chronic kidney disease, acute renal failure and end of life care. London: Department of Health, February 2005.
- Go AS, Chertow GM, Fan D et al. Chronic kidney disease and the risks of death, cardiovascular events and hospitalisation. N Engl J Med 2004;351:1296–305.
- Di Angelantonio E, Danesh J, Eiriksdottir G et al. Renal function and risk of coronary heart disease in general populations: new prospective study and systematic review. PLoS Medicine 2007;4:e270.
- Khoury R, Salmon B, Gandhi A et al. Establishment of eGFR reference ranges in geriatric population using the modification of diet in renal disease study equation. Arch Pathol Lab Med 2007;131:poster 25.
- Tonelli M, Isles C, Curhan G et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation 2004;110:1557–63.
- National Institute for Health and Clinical Excellence. Clinical Guideline 67. Lipid Modification. Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. May 2008.
- JBS 2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005;91(Suppl V):v1–v52.
- Chapman MJ, Assmann G, Fruchart JC et al. European Consensus Panel on HDL-C. Raising
high-density lipoprotein cholesterol with reduction
of cardiovascular risk: the role of nicotinic acid-a
position paper developed by the European Consensus Panel on HDL-C. Curr Med Res Opin 2004;20(8):1253–68.
- Expert panel on detection, evaluation and
treatment of high blood cholesterol in adults. Third report of the National Cholesterol Education Program (NCEP) on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Final report. Circulation 2002;106:3143.
- National Institute for Health and Clinical Excellence. Clinical Guideline 66. Type 2 diabetes. May 2008.
- Ridker PM, Rifai N, Rose L et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002;347:1557–65.
- Danesh J, Wheeler JG, Hirschfield GM et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004;350:1387–97.
- Koenig W. C-reactive protein and cardiovascular risk: an update on what is going on in cardiology. Nephrol Dial Transplant 2003;18:1039–41.
- Pearson T, Mensah G, Alexander R et al. Markers of inflammation and cardiovascular disease. Application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and prevention and the American Heart Association. Circulation 2003;107:499–511.
- Mega J, Morrow D, Cannon C et al. Cholesterol, C-reactive protein, and cerebrovascular events following intensive and moderate statin therapy. J Thromb Thrombol 2006;22:71–6.
- Ridker P, Buring J, Rifai N et al. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women. JAMA 2007;297:611–19.
- Packard C. Improving outcomes through statin therapy – a review of ongoing trials. Eur Heart J 2004;6(Supplement A):A28–A31.
- Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007;370:1829–39.
- B-type natriuretic peptide (BNP) for CHF. Bandolier Mar 2004;121–6.
- Bibbins-Domingo K, Gupta R, Na B et al. N-Terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP), cardiovascular events and mortality in patients with stable coronary heart disease. JAMA 2007;297:169–76.
- Sabatine M, Morrow D, de Lemos J et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes. Simultaneous assessment of troponin I, C-reactive protein and B-type natriuretic peptide. Circulation 2002;105: 1760–3.