Innovative Cardiac Diagnostics - Key to the Total Management of Cardiovascular Disease

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This article is based on the presentations made at the Roche Asia Pacific Cardiology Forum 'Innovative Cardiac Diagnostics: Key to the total management of cardiovascular disease', held in Beijing, China on the 14-15 June 2010. The forum addressed the pertinent issues of the significant and continually increasing burden of cardiovascular disease (CVD) worldwide, the need to better manage patients with CVD and, most crucially, the possibility of using a biologically guided approach to improve the total CV management of patients.

Support: The publication of this report was sponsored by Roche Diagnostics.

Disclosure:Jenny Charlton is an employee of Touch Briefings.



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The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Trends and Diagnostic Advances in Cardiovascular Disease Management

It has long been recognised that the epidemic of cardiovascular disease (CVD) is growing, with ever-increasing incidence and prevalence rates recorded across the globe. In China, as a result of ageing and population growth alone, annual CVD events are likely to increase by over 50% between 2010 and 2050. It is predicted that CVD risk factors in the Chinese population, including hypertension, elevated serum lipids, active smoking, passive smoking and diabetes mellitus (DM), as well as increasing complex comorbidities in the elderly, will only serve to exacerbate the problem (see Figure 1A). James Januzzi (US) opened the forum with his talk on the trends and diagnostic advances in CVD management as it pertains to both the global and more regional cardiovascular crisis.

Given that CVD exacts a considerable cost on society (see Figure 1B), there is a pressing need for improved care of patients suffering from this condition, especially as the burden of CVD is expected to keep rising. The use of biomarkers is now under intense investigation, emerging as a possible means of unifying the prognosis, diagnosis and total CV management of patients. By enabling the detection of CVD at its very earliest stages, such biological measures could afford physicians the opportunity to intervene earlier, potentially preventing overt disease while more skilfully managing established or advanced forms of CVD.

Using heart failure (HF) as an example, Januzzi discussed the concept that measuring NT-proBNP is valuable for diagnostic and prognostic purposes, but could also have the potential to contribute to the universal care of patients with CVD. For example, NT-proBNP measurement may allow the clinician to be able to identify the signs of impending destabilisation before the patient develops signs or symptoms of instability. Evidence suggests that it is possible to detect the presence of HF before the patient develops any symptomatic change or changes in cardiac structure and function. However, what is not yet known is how physicians should act on this information; indeed, clinical algorithms are currently lacking.

Evidence from Januzzi’s laboratory suggests that a single measurement of NT-proBNP can provide useful information about the risk for death and new-onset HF;1 however, monitoring patients with serial measurements over time is superior to a single measurement for predicting risk (see Figure 2). Moreover, as natriuretic peptide (NP) levels change with successful therapeutic intervention, this raises the question of whether NPs could be used to monitor and manage HF therapy. Recently, a study comparing three approaches to patient management (the use of a NT-proBNP biomarker-guided approach; an aggressive multidisciplinary care approach; and usual care) demonstrated a clear separation of risk between the groups. 2

It is also becoming increasingly probable that a multimarker strategy will be required, and the search for biomarkers to compliment NPs has produced several candidates. The combination of highly sensitive cardiac troponin T (hs-cTnT; a marker of myocardial necrosis, a common finding in HF beyond that related to coronary artery disease) and NT-proBNP for prognostication was discussed in later sessions. Another marker of great interest is ST2, which is produced in response to stretching myocytes and appears to correlate tightly with remodelling. In a recent study illustrating how clinicians could respond to an elevated ST2 in a patient with HF or acute myocardial infarction (AMI), patients with an elevated ST2 who received placebo had a large degree of remodelling, as assessed by cardiac magnetic resonance imaging (MRI), whereas those patients who had a high ST2 and received eplerenone (an anti-remodelling agent) did not. 3

The issue of the increase in CVD occurrence was more thoroughly addressed by Dayi Hu (China), with his presentation of data focusing on the epidemiology of CVD, specifically atrial fibrillation (AF), HF and acute coronary syndrome (ACS), in the Chinese population. As is the case in Western countries, CVD is the number-one killer in China, where it accounts for 40% of the total mortality.

There is a high degree of CVD risk factors among Chinese people; approximately 200 million have hypertension; approximately the same number have lipid disorders; the number of DM sufferers was estimated at 92 million in 2010, having risen from the 20 million reported in 2004; and there are an estimated 350 million smokers and an additional 540 million passive smokers.

Reporting the results of a population investigation carried out by his team, Hu found the prevalence of AF in Chinese people aged 30 years or older to be 0.77% (see Figure 3). The greater prevalence of stroke in individuals with AF was discussed, as was the current status of the use of anticoagulation and antiplatelet therapy in such patients. The team found that just 2% of patients with AF were receiving warfarin and 38% aspirin; most (60%) were therefore receiving neither anticoagulation or antiplatelet medication. 4

In China, the prevalence of HF has been reported as a total of 0.9%; it has also been shown to increase with age, to be more prevalent in females than in males, to occur more in northern than in southern parts of China, and more in urban than in rural regions. Hu discussed the changing trends in drug maintenance for Chinese patients with HF between 1980 and 2000 (see Figure 4). 5

Finally, Hu discussed ACS, reporting the results of the Clinical Pathway for Acute Coronary Syndrome in China (CPACS) study. 6 He concluded from the preliminary findings of CPACS (see Figure 5) that early accurate diagnosis and therapy have remained a sizeable challenge for ACS therapeutics in China.

The fact that the definition of MI varies among hospitals, even within Europe and the US, was highlighted by Harvey White (New Zealand). The EHJ/JACC/CIRC taskforce defined five distinct types of MI (see Table 1), with Type 4 [MI associated with percutaneous coronary intervention (PCI)] being the focus of White’s presentation.

The incidence of MI with PCI has varied in studies from 3.6 to 48.8%, and is often considered equivalent to ‘spontaneous MI’ in clinical trials. The ACUITY study aimed to compare the prognostic impact of post- procedural and spontaneously occurring MI on subsequent mortality among moderate- and high-risk patients with non-ST elevation ACS undergoing PCI. 7 In this study, mortality within 30 days was found to be approximately 40% higher with spontaneous MI than with PCI-related MI (see Figure 6). Furthermore, post-procedural MI did not impact on mortality at one year, whereas there was a seven-fold increase in the one-year mortality with spontaneous MI. These data suggest that post-procedural and spontaneous MI should not be considered as equivalent entities, supporting instead the universal definition of spontaneous MI as Type 1 and periprocedural MI as Type 4.

Cardiac Markers in Diagnosis

White began the session on diagnosis with a talk on the implementation of hs-cTnT in clinical practice, stressing that any elevation in troponin, no matter what the setting, denotes a poorer prognosis. Information can be obtained from the detection of very low levels of cTnT; even using a cut-off level as low as 0.01μg/l can be of prognostic value for death and MI at 30 days. 8 The TACTICS trial (an important study comparing invasive versus conservative treatment for ACS) showed that, by using a cTnT cut-off point of 0.01 ng/ml, it was possible to save 10 events (of death, MI or rehospitalisation) per 100 patients.

Biomarker testing has considerable implications for clinical practice, enabling earlier and improved diagnosis, improved risk stratification, as well as the monitoring of antimitotic therapies. High-sensitivity (hs) assays show superiority for patients presenting within three hours of symptom onset, significantly outperforming the older tests. With the new hs tests, it is also possible to rule MI in or out in as little as three hours from symptom onset. 9 Compared with the current algorithm of eight to 12 hours, which often necessitates an overnight stay in the hospital, this would result in huge cost savings and the freeing up of a large number of beds. To judge whether changes in serial testing results reflect true differences, however, the issue of biological variation needs to be taken into consideration. 10 In New Zealand, the use of hs troponin T routinely in clinical practice using an algorithm with 50% change to diagnose MI was introduced (see Figure 7).

Evangelos Giannitsis (Germany) described the superiority of hs-cTnT assays in the acute setting. Three key features of the analytical performance of the hs-cTnT assays that underlie their better clinical performance are: (i) higher analytical sensitivity; (ii) total cardiospecificity; and (iii) improved analytical precision. Thus, the hs tests could enable earlier detection of MI. In a retrospective analysis of a population of patients who were classified as having a negative cTnT on admission using the fourth-generation test, and in whom there was a spontaneous conversion to 100% positivity by six to 12 hours, almost 60% were positive on admission when using the hs test (see Figure 8). 11 A second study supports these results. 12

Elevations in troponin levels can occur for many different reasons, even in the absence of ACS, and the hs tests also have important prognostic roles in diseases unrelated to ACS. Giannitsis presented data in patients with haemodynamically stable confirmed pulmonary embolism (PE), demonstrating that the hs-cTnT was a superior short-term (30-day) risk predictor compared with the fourth-generation test, and was independently predictive even after adjustment for NT-proBNP (the principal biomarker for risk in PE). 13 There are considerations with the hs tests, one of which concerns the reduced specificity that accompanies the lowered diagnostic cut-off point. Using cut-off values of cTnI of >0.1 and >0.006, the sensitivity of the test increased from 55 to 96% on the baseline sample, respectively, whereas the specificity decreased from 93 to 33%, respectively. 14 For this reason, due attention must be given to the differential diagnoses of an elevated troponin level (see Table 2) when interpreting the results of the hs assays. To interpret the results correctly, it is necessary not only to adhere to the universal definition of MI and to carry out serial sampling to demonstrate an acute rise and/or fall, but also to consider the clinical context and biological variability. Taking all this into account, an algorithm has been proposed that is currently in use in Heidelberg University (see Figure 9), where it has been shown to improve the clinical specificity, a significant step forward in the effort to reduce the number of unnecessary coronary angiographies.

Aw Tar Choon (Singapore) discussed the challenges and opportunities of hs-cTnT from the perspective of the processing laboratory team. His busy 800-bed hospital in Changi, Singapore has, despite an increasing workload over the years, managed to reduce turnaround times for cTnT testing. The time from receipt of the sample to delivery of results has been reduced from 57 to just 33 minutes. Choon emphasised the important part played by pre-analytical and post- analytical factors in achieving these reduced turnaround times.

The combined effect of introducing some relatively simple changes, such as right-sizing of staff numbers, introducing one simple request form, intelligent laboratory redesign and upgraded hardware, can make the process more efficient and, thus, dramatically reduce turnaround times. The provision of earlier results enables earlier therapeutic intervention, ultimately contributing to the hospital achieving the fundamental objective of improved patient care. The importance of rapid diagnosis was also explored by Jacob Sørensen (Demark), in his talk on the prehospital diagnosis of patients with ACS. Sørensen discussed how details of the systems in place in Denmark might help others to reduce the time from symptom onset until the patient is treated.

Of ST-segment elevation MI (STEMI) patients in Denmark, 98% are treated with primary PCI through five high-volume primary PCI centres across the country, with maximum transfer distances of 140km. The aim is to diagnose patients as early as possible, ideally in the ambulance. If the patient is suffering from ongoing or recent chest pain, or new-onset shortness of breath, or if the paramedics have a clinical suspicion of an AMI, a prehospital echocardiogram (ECG) can be recorded and transmitted wirelessly to the PCI centre. An on-call cardiologist interprets the ECG and calls the ambulance to conduct a short patient interview and gain any further information from the paramedics. Based on this information, patients are either referred to the nearest hospital with a coronary care unit or are redirected to the catheterisation laboratory, bypassing the local hospital. This system was shown to reduce time from the emergency call to balloon inflation in STEMI patients by as much as 60 minutes. The limitations of this system are for patients with less conclusive ECGs; for example, those with bundle branch block (BBB) infarctions, posterior wall infarctions, pacemakers and previous MIs. Owing to the difficulty in diagnosing these patients, they are often undertreated, and it was thus decided to investigate the use of prehospital biomarkers, as an add-on to the ECG diagnosis.

Although several previous trials in this field have been discouraging of the use of prehospital biomarker sampling, 15,16 these studies used prehospital biomarkers more or less as a stand-alone diagnostic tool for AMI, rather than as an addition to ECG assessment. A recently completed feasibility study conducted by Sørensen and his colleagues demonstrated that ambulance paramedics were able to perform blood sampling at an acceptable success rate. The results of the study strongly suggested that prehospital biomarker sampling is feasible in the hands of paramedics and that by using a qualitative test kit, it is possible to influence triage.

Early Assessment

Christopher deFilippi (US) explained that when applying traditional risk models, such as the Framingham Risk Score, for predicting outcomes in Caucasian men or women, results are more accurate for younger individuals than in elderly cohorts. 17 The role of novel biomarkers in addition to the application of these models has been explored, with a landmark study from the Framingham Group being the first to demonstrate that, in a large observational cohort and otherwise asymptomatic ambulatory middle-aged population, those with the highest levels of BNP were at an increased risk for a variety of CV end- points, as well as the overall risk of death. 18 There were, however, several methodical and assay issues with the study, and a follow-up study demonstrated no benefit to the addition of biomarkers to augment risk stratification.19 Furthermore, in a more recent study of a normal healthy subgroup of patients, NT-proBNP was not shown to be predictive of any particular end-point.20 By contrast, in those who had underlying risk factors or some evidence of underlying structural heart disease, division based upon the 80th percentile for NT-proBNP was able to stratify participants into two risk groups.20 A recent meta-analysis found that, in middle-aged or older middle-aged populations, the addition of NT-proBNP to conventional risk factors did not add to the predictive power; however, in older individuals or those defined as having elevated risk, predictive value was seen (see Table 3).21

In the Cardiovascular Health Study (CHS; a large, multicentre US study of 5,888 individuals aged 65 years or over), NT-proBNP was measured at entry and again two to three years later, and incident HF and CV mortality were recorded.22 Higher levels of NT-proBNP were associated with increased risk for developing HF over long-term follow-up, and similarly for CV death, even when looking at levels below the cut-offs that might be associated with HF. NT-proBNP was shown to improve predictions of new-onset HF in the elderly (see Figure 10) and to identify those at greatest risk for developing an abnormal ejection fraction (EF). The study also showed that serial testing over the study period further refined risk prediction, suggesting a limited role for adjunctive assessment to NT-proBNP for further risk stratification of left ventricular EF (LVEF), at least in an asymptomatic general population at risk, such as the elderly.

Ping Ye (China) spoke about his recent study investigating the relationship between circulating biomarkers and arterial stiffness (an important determinant of CVD) in a large community-based Chinese population (n=1,680). Conventional clinical data, such as age, gender, blood pressure, lipids, glucose and body mass index (BMI), were recorded for the randomly assigned patients. Plasma homocysteine, NT-proBNP and hs C-reactive protein (hs-CRP) were also measured. Arterial stiffness was assessed by the carotid-femoral pulse wave velocity (PWV), carotid-radial PWV, carotid-ankle PWV and the central pressure augmentation index. Not yet published, Ye’s univariate analysis of the total population data showed that each of the three biomarkers correlated with arterial stiffness; however, after modelling with other covariants, and following sex-specific multiple linear regression analysis, only homocysteine was independently predictive of aortic stiffness in men, even after controlling for age and other conventional CV risk factors. Follow-up investigations are planned to evaluate the role of hs-cTnT; Ye and his colleagues will look at the associations between homocysteine, NT-proBNP, hs-CRP and hs-cTnT measurements and mortality and/or CV events by long- term follow-up. They also intend to evaluate the prognostic value of different plasma biomarkers in risk-assessment and risk-reduction strategies in the Chinese population.

The crucial role of point-of-care (POC) technology in improving population outcomes in CVD was highlighted by Philip Tideman (Australia). South Australia covers nearly a million square kilometres, but has a population of just 1.5 million, and Adelaide accounts for approximately 1 million individuals; thus, the population densities in rural areas are extremely low. Data from a population health study published almost 10 years ago demonstrated that improvements in coronary heart disease (CHD) outcomes were not uniform, with CHD mortality 30% higher in men and 21% higher in non-metropolitan areas compared with metropolitan settings.23 To address this discrepancy, the Cardiovascular Clinical Network began putting in place several tools to facilitate the delivery of evidence-based cardiac care to the geographically isolated rural populations of this state. Integrated clinical pathways were drawn up to help guide risk stratification, management and triage of patients, with POC pathology implemented in all hospitals, initially the Roche Cardiac Troponin T reader and, more recently, the Cobas platform. A 24/7 system of consultant cardiologists was available, not only to provide ECG interpretations, but also to give clinical advice regarding individual patients. Single-bolus tenectplase as the drug of choice was made universally available to all hospitals, and staff training and continuing medical education (CME) to improve the skills of the doctors and nurses was provided.

The Network began implementing changes during the mid-1990s and, in the 10-year period that followed, the in-hospital ACS death rate declined significantly. In fact, data for the next two years (not presented here) have shown that there is no longer any statistically significant difference in the ACS in-hospital death rates between the trial group and a metropolitan control population. The combination of POC testing for cardiac markers and integrated treatment and triage protocols, which have enabled more patients access to evidence- based acute cardiac care for ACS outside of metropolitan areas, has demonstrated that POC testing might be an enabler of evidence-based medical management and, when applied as part of a widely integrated system, can have significant impacts on the delivery of patient care.

The vague and non-specific clinical symptoms of HF contribute to the difficulty in diagnosing this condition, and there is a need for objective tools to provide more accurate diagnoses and to better assess the clinical severity of HF. In fact, studies have shown the fraction of falsely diagnosed HF in primary health care to be 40–50%24 and 26% in the emergency department (ED).25 Anwar Santoso (Indonesia) discussed the clinical application of biomarkers and ECGs in HF diagnosis. Among other results, a negative correlation between the EF and NT-proBNP has been demonstrated,26 as has a positive correlation between BNP and the end-diastolic pressure, systolic wall stress and end-diastolic wall stress (EDWS).27 Other data have demonstrated a positive correlation between the level of BNP and parameters of diastolic dysfunction.27,28 The concentration of NT-proBNP has also been shown to be grossly elevated in PE, and levels of NT-proBNP can be used for risk stratification in such patients.29 Thus, the combination of an NT-proBNP measurement with one or more other modalities can give better predictions of the clinical outcome, both in PE29 and in HF.27 In fact, a clinical algorithm for the integrated use of BNP and ECGs for HF diagnosis has been drawn up and should be considered for use in clinical practice (see Figure 11).

Risk Stratification and Prognosis

The cost effectiveness of any additional resources is particularly important and Alan Fong (Malaysia) discussed his experience of the cost-effectiveness of using NT-proBNP in the management of acute HF in a public hospital. Fong’s single-centre retrospective study in a secondary care facility of 80 patients hospitalised for acute decompensated HF (ADHF) between May and July 2003, demonstrated a rate of 7.5% for in-patient mortality or urgent transfer to a tertiary care centre for subsequent treatment.30 More contemporary data from the ADHERE registry (a multicentre prospective data collection of district general and tertiary centres carried out over three years in Malaysia between 2006 and 2009) still showed in-hospital mortality to be 7.6%. This latter study did, however, find a improvement in discharge medications, with over 50% of patients on angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), 81% on diuretics, approximately one-third on digoxin and increasing numbers on spironolactone (31%). More recently, Fong and his colleagues carried out a single-centre, cost-effectiveness study looking at NT-proBNP in the assessment of patients admitted with acute dyspnoea. In this prospective controlled study of 160 patients admitted with breathlessness, 80 patients in the historical control group had been subjected to a conventional diagnostic strategy that included a chest X-ray and ECG (in accordance with the 2007 Clinical Practice Guidelines) and 80 patients had NT-proBNP assays in addition to the standard diagnostic strategy. The trial group had improvements in the primary outcomes, with the mean length of hospital stay reduced from 6.67 to 5.34 days (p<0.001) and the mean direct cost of treatment reduced from approximately US$72.8 to around US$55 (p=0.007). The results of this study show that the addition of NT-proBNP can improve the clinical evaluation and treatment of patients presenting with acute dyspnoea, leading to reductions in the length of hospitalisation, the direct cost of treatment as well as the total cost of management.

Improved primary outcomes in the in-hospital mortality rate, mortality rate and rehospitalisation rate at six months was also seen in congestive HF (CHF) patients in a study by Kriengkrai Hengrussamee (Thailand). The study examined the prognostic yield of NT-proBNP in ADHF patients. The adult patients admitted to one of the nine participating cardiac centres in Thailand all had dyspnoea that was initially diagnosed as ADHF. The study, which began in November 2009, is planned to end in December 2010. Although it has not yet been completed, the initial findings suggest that levels of NT-proBNP appear to be higher in sick patients (i.e. those with New York Heart Association [NYHA] class III & IV) and reach statistical significance in those with low LVEFs and coronary artery disease (CAD) compared with those having preserved LFEFs and non-CAD, respectively.

More data suggesting that preoperative levels of NT-proBNP and CRP are able to predict perioperative major CV events in noncardiac surgery were presented by Eun-Seok Jeon (Korea). Preoperative evaluations by clinical examination and measurement of biomarkers were carried out in 2,054 elective noncardiac surgery candidates within the four weeks before surgery. Following surgery, patients were followed until discharge or the end of a 30-day post-operative period. The primary end-point (a major CV event within 30 days, including AMI, the development and/or aggravation of HF and primary CV death) was shown to have a significant dose-response relationship between the risk predictors of the modified Revised Cardiac Risk Index (RCRI), NT-proBNP and CRP and the clinical outcome, not only for the primary end-point, but also for AMI, HF and CV death. For the prediction of major cardiac events, both NT-proBNP and CRP were superior to the RCRI, and predictive power was increased through the combination of multiple risk predictors; when compared with the RCRI alone, the addition of a single biomarker (NT-proBNP or CRP) significantly increased the area under the curve (AUC). Moreover, the addition of both biomarkers to the RCRI further augmented the predictive power, and this was also observed for AMI, HF and CV death. The most important limitation, relating to the study population, was that only the most high-risk patients were included, thus the data from this study might not reflect the true incidence of in-house perioperative CV events.

A simple method for predicting mortality in ambulatory patients with CHF is the MUSIC risk score, discussed by Antoni Bayés-Genís (Spain). Predictor models for mortality in HF are crucial and, following the ACC/AHA 2005 guidelines, which stated that ‘because treatment of CHF has improved over the past 10 years, the older prognostic models need to be revalidated’, several groups have set out to develop newer prognostic models.

The Seattle Heart Failure Model,31 for example, is a very robust model derived from a large cohort of patients from a multicentre clinical trial and validated in other patient cohorts. With the growing understanding of the importance of biomarkers in risk stratification, NPs have recently been incorporated into this model. Another model, derived from the CHARM cohort,32 also examined predictors of morbidity and mortality in patients with CHF. However, some of the variables used in this model are not very well defined, and it is not particularly suitable for day-to-day clinical practice. Bayés-Genís and his colleagues designed the MUSIC study (a prospective multicentre longitudinal trial to assess mortality predictors in ambulatory patients with HF). The aim of the study was to assess which risk predictors were useful in predicting global cardiac mortality, sudden HF death and pump failure death. In all, 992 patients with NYHA class II–III CHF were consecutively enrolled and treated according to current guidelines. The protocol was fairly simple; all subjects had clinical, ECG and blood laboratory parameters, and Holter monitoring, performed at enrolment, and follow-up visits were conducted every six months, for a median of 44 months. It was possible to predict mortality in patients with HF using a simple scoring system, including a limited number of predictors. Indeed, this prognostic assessment could be conducted with just 10 predictors: one clinical variable (previous vascular event); two ECG variables (dilated left atrial size [>26 mm/m2).] and low LVEF [<35%]); three electrical variables (AF, combined bundle branch block or intraventricular conduction defects, and non-sustained VT plus frequent ventricular premature beats); and four biochemical variables [hyponatraemia (>138mEq/l), high NT-proBNP (>1,000ng/l), troponin positive (>p99) and eGFR below 60ml/minute/1.73m2). All these predictors are noninvasive, cheap and objective variables, so this model could be easily used in clinical practice. Indeed, use of this model identifies a small subgroup of high-risk patients that should be managed closely by specialist HF units.33 deFilippi addressed the question of whether renal function affects the interpretation of NPs; previously, the subject of much controversy. It seems this question has now been definitively answered, with evidence strongly suggesting that renal function does not, in fact, influence the levels of NPs. Studies have shown that both in patients with ambulatory chronic kidney disease (CKD) and in populations with impaired renal function presenting with dyspnoea, there is a modest but generally significant correlation, whether of NT-proBNP or BNP, with the estimated glomerular filtration rate (eGFR).34

Both peptides can be detected in the urine and, in a study of individuals with normal renal function, the renal fractional extraction ratio for NT-proBNP and BNP was shown to be identical.35 Another study in individuals predominantly being evaluated for hypertension showed that, across a broad spectrum of renal function, the renal extraction ratio was similar and did not differ significantly for NT-proBNP and BNP.36 For more critically ill patients who had indications for pulmonary artery catheters, whether there was more normal or impaired renal function, for any given BNP or NT-proBNP value, there was a broad range of pulmonary capillary wedge pressures.37 If the renal function was more impaired (defined by an eGFR <60), the correlation between the pulmonary capillary wedge pressure and the NT-proBNP and BNP was poorer compared with those with more normal renal function.

In a Japanese study of patients undergoing left heart catheterisations, there was a moderate correlation between BNP and this direct measure of congestive LV end-diastolic pressure, and there was a large degree of scatter for any particular pressure.

However, when the investigators calculated the EDWS, thus taking into account wall thickness, the dimension of the LV and systolic pressure, there was a tight correlation between BNP and the EDWS.38 In 2009, the team extended their findings to include individuals who had CKD, who were not on renal replacement therapy, and patients with ESRD who were on dialysis.39 They found that, for patients who had CKD not requiring dialysis, there remained a good correlation between wall stress and NP levels.

Looking at the clinical applications of NPs in patients with renal disease, it is possible to obtain good sensitivity and specificity with NT-proBNP in patients presenting to the ED with dyspnoea, differentiating between an acute and a non-acute decompensated HF etiology.40 Both the ICON and the GUSTO-IV studies clearly demonstrated the synergy between an elevated NT-proBNP level and impaired renal function; those with impaired renal function and NT-proBNP above the median had by far the poorest prognosis.8,41 An association of higher NT-proBNP with underlying CV comorbidity in asymptomatic renal patients has been demonstrated.42 Moreover, NT-proBNP has prognostic value in such patients; in a study of asymptomatic African-Americans with CKD and hypertension, those in the highest group had a greater risk of having a CV event or dying over the follow-up period of several years.43

The utility of cTnT in patients with CKD was further examined by Angela Wang (Hong Kong). The link between renal dysfunction and cardiac disease is gradually being recognised and a recent paper redefined cardiorenal syndrome (CRS) to stress the bidirectional nature of heart to kidney interactions, and reclassified CRS into five types (I–V).44 In 2007, a study from Wang’s group found the prevalence of CVD in prevalent dialysis patients to be alarmingly high; most of the patients had cardiac hypertrophy, and 80% had diastolic dysfunction.45 Over the past 10 years, many studies have looked at the cTnT elevation in patients with CKD, and this biomarker has proven to be a robust risk predictor in this patient group. Wang and her team were able to show that, despite being confounded by inflammation, residual kidney function or cardiac hypertrophy, cTnT remained powerfully predictive of mortality, CV death and events in patients receiving peritoneal dialysis.45 Further work by this team clearly indicated the superiority of cTnT over CRP as a risk predictor in the ESRD population.45 Wang’s team have also shown it to be useful in identifying patients at risk of HF,19 demonstrating that cTnT could be utilised in a clinical setting to identify patients with ERSD at high risk for CV events and HF. More recently, in a five-year prospective follow-up study, Wang’s team have been studying whether a single one-off measurement of cTnT might be useful for predicting patients at risk of sudden cardiac death.46 There is now convincing clinical evidence to demonstrate the importance of cTnT in predicting outcomes in patients with CKD, and the 2007 National Academy of Clinical Biochemistry (NACB) Guidelines recommend the use of cTnT in such patients.47 Elevated cTnT in patients with stage 5 CKD is likely to be indicative of myocardial injury, although it does not identify the mechanism of the injury, and predicts an increased risk of death, CV events and HF. Moreover, measurement of cTnT is warranted for evaluating AMI in patients with CKD, and the universal definition of MI should be used in such patients.

Finally, it is important to understand whether troponin in risk assessment extrapolates to ACS and chronic CAD in the community. White discussed a recent paper by the TIMI study group that found, in patients with suspected ACS, low-level increases in cTnI (below the current cut-off point) could identify patients at higher risk of death or MI.48 The demonstration that there is prognostic information to be found below the contemporary cut-off point in patients with CAD was also shown in the PEACE trial, which included 3,679 patients with stable CAD. After adjustment for other independent prognostic indicators, cTnT concentrations as measured with a hs assay were significantly associated with the incidence of CV death and HF, but not with MI in this patient group.49 The results of these two studies substantiate the concept that minimal levels of myocyte necrosis (resulting in low-level hs circulating troponins) can predict adverse outcomes.

A recent study, which used the Framingham Risk score, included 1,072 middle-aged men working in a factory and found that 80.9% had elevated hs-cTnT,50 although the highest level recorded was 20ng/l, well below the current cut-off point of 53ng/l for the contemporary cTnT assay. Elevated troponin in this population was significantly associated with hypertension, obesity, LV hypertrophy, current smoking status and CKD, but not with dyslipidaemia, DM or a family history of CVD. Individuals in the highest tertile compared with the lowest tertile had an odds ratio for highly predicted CVD risk (10-year risk ≥20%) of 3.98 (95% confidence interval [CI] 1.72–9.24; p=0.001].

Studies have shown that combining the two markers (NT-proBNP and cTnT) affords additive risk stratification. In the FRISC study, in addition to one measurement, a delta NT-proBNP from presentation to 72 hours afforded enhanced risk stratification.51 The FRISC II study explored the feasibility of using NT-proBNP and cTnT to guide ACS therapy.52 Januzzi’s team have also been exploring the possibility of adding other biomarkers to augment the diagnostic yield of troponins. Januzzi presented some unpublished data from a prospective multicentre trial in which patients with ACS were enrolled and panelled for a wide range of biomarkers including, among others, hs-cTnT, NT-proBNP, ischaemia-modified albumin, free fatty acids and fatty acid binding protein. The results, expected to be published shortly, are likely to show that, among the few markers that actually had any diagnostic merit, NT- proBNP added to cTnT for the diagnostic evaluation of chest pain.

Therapy Monitoring

It has now been well established that the concentration of NT-proBNP in chronic HF is powerfully prognostic and that serial measurements over time are superior to one single measurement with respect to predicting the likelihood for adverse outcomes (see Figure 2).53 As an overall barometer for heart function, NT-proBNP provides a wealth of information, correlating well with many measures of cardiac structure and function. In terms of the clinical management of patients, a biological signal such as NT-proBNP has emerged as a plausible means of detecting the likelihood of instability before its onset and may serve as a target for therapy.

Januzzi described how, before evaluating the approach of NT-proBNP guidance for the management of HF, several factors need to be taken into consideration. First, it is necessary to establish a target level of NT-proBNP in HF, which was determined on the basis of the threshold of risk to be 1,000pg/ml. Second, there must be a consideration of biological variability and, in chronic HF, a rise or fall of 25% is considered to be a significant change. In terms of how to approach an elevated value, NT-proBNP and BNP levels are, fairly universally, reduced in parallel with the clinical benefit provided by HF therapies; thus, importantly, they provide a biological measure of response to therapy. It is crucial, however, that NP testing is used as an additive to clinical judgement, not a substitute for it. The timing of the sampling is also crucial, and the optimal time-point for resampling following a change in therapy has been calculated to be about two weeks,54 which provides a convenient synergy with standard clinical practice.

Several trials have examined the outcomes associated with guided therapy. On the surface, these are essentially split 50:50 with respect to being positive versus negative for the use of NT-proBNP guidance. A closer look at the design of these studies, however, reveals reasons for such a split of positive versus negative.

The earliest study, conducted by Richard Troughton from Christchurch and published in The Lancet in 2000, found that outcomes (hospitalisation and death) were significantly reduced by NT-proBNP guidance.55 By contrast, STARBRITE, the first US-based study of this kind, which looked at BNP guidance for HF therapy, was negative, concluding there to be no benefit on outcomes associated with guided therapy. This latter study, however, selected the BNP level at discharge from hospital as the therapeutic target value in patients with recently destabilised HF. This value is almost routinely far too high, which casts doubt over the validity of the conclusion drawn. Two other trials (BATTLESCARRED and the TIME-CHF study) were also negative, reporting no benefit with respect to the outcome of guided therapy; however, subgroup analyses of the data reveal a rather different picture. For patients under the age of 75, BATTLESCARRED showed a mortality reduction at one year, two years and three years associated with NT-proBNP guidance when compared with primary care physician (PCP) management of HF and aggressive management of HF by HF specialists (see Figure 12). Moreover, despite the overall negative primary end-point of TIME-CHF, substratifying on the basis of patients less than 75 years old reveals guided therapy to be associated with a significant improvement in both survival and HF hospital-free survival.56 The remaining question in terms of BATTLESCARRED and TME-CHF is whether elders are not eligible for therapy ‘guided’ by NT-proBNP, or whether such guided therapy in elders should be delivered differently in younger patients, perhaps more gradually.

Recent trials have been more positive; in a group of patients largely with systolic HF who were randomised after discharge from the hospital to either PCP care, a multidisciplinary nursing care follow-up approach or multidisciplinary care together with NT-proBNP guidance, significant reductions in NT-proBNP were seen in the biomarker-guided group.2 The recently completed PROTECT study, which examined patients with HF with class II–IV symptoms, also documented significant reductions in cardiovascular event rates related to NT-proBNP guidance with a goal value of <1,000pg/ml.

There remains the question of whether aggressive uptitration of medications in patients with HF should be instigated anyway, with or without NT-proBNP guidance. However, given that most HF care is not in the hands of HF specialists, the addition of a biological measure to help guide the uptitration of medication would be of great value for PCPs. Furthermore, as Dr Januzzi concluded, a more ‘biological’ approach to patients with chronic HF is clearly in the future of this growing area of cardiovascular disease.

Marcel Levi (The Netherlands) and Yong Seoh Oh (Korea) used therapy monitoring with respect to anticoagulant treatment as an example to raise the issue of patient self-management. Warfarin (a vitamin k antagonist anticoagulant) has now been in use for 65 years, and an estimated 10 million individuals are currently using the drug worldwide, with this figure increasing in Western countries, especially so in Asia. Much of this increase can be attributed to the fact that one of the main indications for vitamin k antagonists is AF; with an ageing population and increasing physician awareness of AF, the number of patients using warfarin is ever increasing. The growth rate of AF is estimated to be 2% per year, with almost 1% of the population and 8% of the very elderly population (over 80 years) currently affected by the condition.

A recent consensus paper lays out the advantages and disadvantages of the various anticoagulant treatment options in patients with AF57 and, although oral anticoagulation with vitamin k antagonists reduces thromboembolic complications in most patients, many patients with AF do not receive this treatment. Risk reduction in thromboembolism is, however, accompanied by a concomitant increase in major bleeding complications. In fact, one of the biggest limitations of warfarin is that a larger number of factors can affect its metabolism, altering the concentration of the drug in the body. Owing to this, it is not possible to assume that it is exerting a steady effect, making it necessary to frequently check the international normalised ratio (INR) and possibly adjust the dosage when needed. To realise the effectiveness of anticoagulants, therefore, the therapy must be monitored and it is crucial to keep patients within the therapeutic target range. An international study found that just 50–60% of patients were within the therapeutic target range at any given point in time.58 Self management is an option that seems to be feasible59 and, in a large German study of patients with AF, self-management was in fact shown to be more superior than the usual care.60 Furthermore, a large Spanish study reported more complications in the conventional management group as compared with the patient self-management group.61

Oh briefly discussed the experience at his hospital of patient self- testing (PSR) in INR monitoring. Previous comparisons between the CoaguCheck® XS (Roche; a coagulation system specifically developed to enable near patient testing of coagulation levels) and central laboratory testing have demonstrated no significant differences between the data obtained.62,63 Owing to this background of promising comparison, in September 2008, Oh introduced the CoaguCheck® systems into his own hospital. The benefits of the new system were many-fold, increasing patient satisfaction through saving time, reducing the INR testing time from one hour to one minute, saving blood, from 10cc to one drop and resulting in fewer complications relating to vein punctures, such as pain, haematomas and infections.

The CoaguCheck® monitoring system provides an economic benefit and makes possible the long-term follow-up of patients. Importantly, with the system, patients are able to measure their INR remotely, at home for example, then call the hospital and receive advice from the anticoagulation clinic as to how to adjust their dosage to reduce the risk of falling out of their therapeutic range. This feature also results in a cost saving to patients as they do not need to visit the hospital so frequently. No complications relating to the INR check were observed using the CoaguCheck system, and no side effects or stroke occurred in any patients within the therapeutic range of INR. This applied both to the in-hospital use of the test as well as INR self monitoring. There are several factors that make self monitoring attractive, some even necessitate the use of INR self monitoring. These include living a long distance from the hospital, travelling abroad, physical problems such as stroke, severe arthritis, injury of extremity, dementia, experiencing side effects of warfarin and being sensitive to the drug, among others. Thus, in the long term, patient self monitoring, especially in remote regions, could have a major impact on treatment regimens.


This meeting of international experts gathered to explore and share knowledge on the value that diagnostics can bring to the quality of care for CVD patients. Despite having an increasingly important role in the clinical management of patients with CVD, diagnostic testing is nonetheless under-utilised across the world and, in particular, in Asia. During the meeting trends and diagnostic advances in cardiovascular disease management, including recent data on various cardiac markers, were discussed and valuable discussions concerning their use for early assessment, risk stratification and prognostic assessments were also held. The future appears to be evaluating these markers for use in therapy monitoring and translating the application of the diagnostic tool into the treatment pathways to see benefits for patients.


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