Ana Gallardo, Steve Howell and Alan Clark look at how near-patient or home diagnostic tests based on biomarkers have the potential to change the way cardiovascular diseases are monitored and treated
The past few decades have seen a steady refocus on the approach to disease diagnosis and treatment. From the traditional role of the clinic or hospital as the centralised location for diagnosis and therapy, there has been a progression to a greater emphasis on home diagnostics and individually tailored therapeutics on the basis of soaring healthcare costs and demands for patient empowerment.
Advances in technology and public acceptance have allowed this shift to personalised medicine, which relies on the correct choice and application of biomarkers specific to particular medical conditions. The key to successful home diagnosis and monitoring lies in the user-friendly combination of a sensitive and specific biomarker with a technology platform able to detect, measure and differentiate such a biomarker within acceptable diagnostic levels in a rapid, reliable manner.
biological indicator
The clinical and diagnostic value of a biomarker lies in its direct link to a specific biological process. Measurement of its presence in a patient can provide an indication of pathogenic processes or, following treatment, of the pharmacological response to therapeutic intervention. The combination of a good biomarker with an appropriate platform technology constitutes a very powerful diagnostic tool.
Self-testing for certain conditions involves using different body fluids - blood and saliva being the most common. Blood glucose sensors and pregnancy tests have revolutionised home monitoring (the first patent for a blood glucose meter was granted in 1971). Products developed for male and female fertility testing have also seen a transition from testing in the clinic to testing in the home.
One area where home diagnostics is showing great promise and growth is in cardiology - the shift of emphasis within the medical community towards prevention rather than cure is already manifest in the growing number of devices such as lipid monitors and cholesterol readers that have appeared in the market. The trend is to empower potential patients with the appropriate information and tools for them to adjust their lifestyle to prevent the appearance of cardiac disease.
The increasing number of identified cardiac biomarkers, our improved understanding of their functions and the availability of technical solutions for their measurement and interpretation make home monitoring a very valid option for cardiovascular patients. From drug titration to monitoring chronic patients, self-testing is the answer in an ageing society where good patient management is proving to be more effective than critical emergency treatment post-incident.
A good example of this is in the monitoring of Warfarin anticoagulant for the treatment and prevention of venous and arterial blood clots. Anticoagulation monitoring has played a key role in the transition from centralised treatment in clinics and hospitals towards a personalised approach where patients are responsible for titrating their own anticoagulant treatment.
close control
Warfarin is an effective anticoagulant, but requires routine monitoring due to its narrow therapeutic range. Chronic Warfarin therapy is normally required in patients with mechanical heart valves and in some patients with chronic atrial fibrillation or similar conditions with a high risk of blood clot formation. Warfarin works by slowing down the blood's ability to form clots, and its use needs to be closely controlled to maintain the blood's clotting time within a narrow window in order to avoid complications and potentially fatal side-effects.
Appropriate levels of Warfarin anti-coagulation are monitored with periodic prothrombin time (PT) measurements. Prothombin is a precursor of thrombin, which converts fibrinogen into fibrin, a key step in the blood clotting process. PT measurements determine the time it takes for the blood to clot. The clinical impact of home PT measurement is directly related to improved Warfarin therapy management. Home testing allows for more frequent monitoring and self-management of Warfarin intake, which translates into increased time that the anticoagulation is within a therapeutic range and decreased risk of thrombo-embolic or hemorrhagic events.
personalised care
There are several devices approved by the US Food and Drug Administration (FDA) available in the market for home monitoring of chronic anticoagulant therapy. The FDA approval for these devices is based on the demonstration that appropriately trained patients could generate test results comparable to laboratory measures. Coagulation analysers for patient self-testing PT to optimise Warfarin therapy are testimony to home testing being a step towards personalised medicine.
Not only can the patients keep track of their PT but the devices allow continuous customisation of the appropriate drug dosage to suit the individual patient's needs at the time the test is made. Furthermore, the FDA published a preliminary draft concept paper in 20051 that outlined its thoughts on how to prospectively co-develop a drug or biological therapy (drugs) and device test. The integration of such a drug/test combination in areas beyond anticoagulation will ultimately give significant clinical benefit to patients.
Coagulation monitoring is a breakthrough model and it shows evidence of the benefits of home testing in diagnosis and treatment. However, each particular disease condition presents a new set of scientific, sociological and market challenges to the application of home monitoring.
According to the World Health Organisation, cardiovascular diseases are responsible for 17 million deaths worldwide each year and are the main killer in Western society.2 Many of these deaths could be avoided with more specific, more reliable, more sensitive and faster diagnostic techniques to allow earlier treatment and better long-term prognosis. It is not surprising, therefore, that many life science companies have already recognised the high market potential of near-patient diagnostics in the cardiac arena. The concept of rapid testing in a clinical environment is well known and there is much evidence of applications for different cardiovascular conditions using relevant biomarkers (iSTAT, triage, etc). However, the challenge of introducing them for use in the home environment remains.
Coronary Heart Disease (CHD) is the most common type of heart disease and occurs when the coronary arteries become hardened and narrowed through the thickening of their inner walls. Eventually the reduction of blood flow, and therefore oxygen, to the myocytes (cardiac muscle cells) results in Myocardial Ischemia (angina), which can progress to Myocardial Infarction (MI) when necrosis of myocardial tissue appears. Over time CHD can weaken the heart muscle and contribute to arrhythmias and the onset of Chronic Heart Failure (CHF).
Cardiac test panels have traditionally been based on the detection (quantitative or semi-quantitative) of markers for myocardial necrosis, such as cardiac troponin I (cTnI), creatine kinase-MB (CK-MB) and myoglobin. Of these, myoglobin presents the highest clinical sensitivity in the first six hours after the onset of chest pain; CK-MB remains sensitive for 48hrs while cTnI stays highly sensitive for up to 72hrs.3 Moreover, cTnI can also be used for the late diagnosis of MI because elevated concentrations can be detected 5-8 days after onset. Although the characteristics of cTnI, CK-MB and myoglobin are highly complementary and, therefore, are usually incorporated into one test, cTnI is a well respected marker in its own right and commonly used for corroboration of electrocardiogram (ECG) results in emergency hospital environments.4
early diagnosis
Despite their indisputable clinical value, cTnI, CK-MB and myoglobin are thought to be released only after irreversible myocardial necrosis, thus tests based on them will appear negative when performed on patients suffering from acute coronary syndrome (ACS) within the first three hours from onset of chest pain. Identification and appropriate detection of biomarkers released early after the onset of symptoms is therefore critical to enable early diagnostic and therapeutic decisions.
B-type Natriuretic Peptide (BNP), N-terminal BNP (NT-proBNP) and Ischemia Modified Albumin (IMA) are considered early risk predictors in patients with angina. Furthermore, IMA in conjunction with cTnI and an ECG is the only FDA-approved rule-out test for ischemia. BNP and NT-proBNP have also proved to be not only good indicators of CHF, but also of early ACS.
ventricular overload
BNP is a small peptide (32 amino acids) secreted by heart myocytes to increase regulation of blood pressure and fluid balance. This peptide is synthesised by ventricular cells and stored as a pro form (108 amino acids). Upon secretion in response to ventricular expansion or pressure overload, the pro form is cleaved, releasing the 32 amino acid active BNP and an N-terminal piece of 76 amino acids (NT-ProBNP). Both BNP and NT-ProBNP are, therefore, markers of ventricular distension and overload.
This relationship is important in patients with congestive heart failure. Moreover, NT-proBNP provides critical prognostic insight to the assessment of ACS patients, even those with a non-conclusive ECG.5
The conformation change in human serum albumin (HSA) caused by ischemia6,7 has been recently assessed as an early marker of myocardial ischemia. Such a variation is assessed through measuring the ability of albumin molecules to bind transition metals. During an ischemic event, the transformation of HSA into IMA results in a decrease in binding capacity and this forms the basis of the diagnostic test. Although the precise mechanism and cause are still unclear, this could be a result of hypoxia, acidosis, free-radical injury and energy-dependent membrane disruption.8
Although IMA is currently widely employed together with ECGs and cTnI as a rule-out test for ischemia, the challenge remains to design a relevant test capable of ruling in patients based on IMA results. This is the critical step towards a successful move to home testing environment for early markers of ischemia, which would enable chronic patients to monitor their condition on a regular basis and to identify emergency situations as early as possible by self-testing for IMA rise when chest pain appears.
Angina can progress into infarction with tragic consequences in the space of 48-72 hrs, therefore proper early treatment of unstable angina has a critical effect on survival rates.
silent ischemia
Patients with previous history of cardiac disorders are not the only beneficiaries of rapid home cardiac tests. Home testing could be revolutionary in the detection and treatment of silent ischemia, particularly in undiagnosed healthy individuals.
The American Heart Association (AHA) estimates that 3-4 million people in the US may have ischemic episodes without knowing it or experiencing any pain. This is referred to as silent ischemia and victims could develop myocardial infarction with no prior warning. In fact, cardiomyopathy (heart muscle disease) caused by silent ischemia is among the more common causes of heart failure in the US. People who have had previous angina episodes could have undiagnosed episodes of silent ischemia, but also at risk are diabetics, smokers, individuals suffering from high blood pressure, obesity and alcohol and drug abuse.
Exercise tests and heart monitors are currently used in the diagnosis of silent ischemia. The first determines the blood flow of the coronary arteries at stress (during exercise) - an indicator of general coronary health - and the latter records the rate and rhythm of the heart over a 24-hour period. This means that silent ischemia episodes would be detected only if taking place during that time window. An IMA home testing device used daily could detect any silent ischemia episodes in minutes.9 As early episodes of silent ischemia are normally not treated with medication but by lifestyle changes, IMA home tests could prevent any serious cardiac episodes and decrease the number of patients in need of drug treatment, thereby decreasing health costs and improving the patients" quality of life.
responsibility shift
Home testing has its own set of challenges to meet. Not only is it critical to find and isolate the right biomarkers that signify a certain condition, it is equally fundamental to design a technology platform that enables accurate and rapid differentiation of such biomarkers within the limitations of the home environment. The user is no longer a health professional, but a patient taking responsibility for self-monitoring their condition.
This means that tests need to be user-friendly and fully integrated, with minimum handling required from the user, i.e. no preparation steps; avoidance of temperamental reagents that might be affected by mishandling, etc.
It is also important that the device is implemented with the right processing tools to allow reporting of results in an unambiguous and easy to interpret manner. Testing should become a regular occurrence in patients" lives, which is more likely to happen if devices are discreet and portable. Moreover, tests that are to be performed regularly should be minimally invasive and must be designed to be fully functional with minimum sample volumes of no more than a few microlitres of whole blood. This requires extensive design and development of critical fluid handling solutions.
In summary, home test cardiac devices have the challenges of enabling precise, accurate and sensitive measurements based on small fluid samples, and of providing user-friendly and ease-to-interpret results. Furthermore, these instruments could potentially be able to perform additional computations or be connected with a centralised clinic where the results would become part of the full clinical history of the patient.
Diagnostics innovation programme
ITI Life Sciences is one year into a three-year funding programme with Inverness Medical Innovations (IMI) focused on identifying novel biomarkers and home tests for cardiovascular disease. IMI has created a subsidiary company in Stirling, Scotland, called Stirling Medical Innovations (SMI), which aims to be a centre of excellence in cardiovascular diagnostics and is attracting expertise from all over the world. The outcome of the programme is aimed at home diagnostic testing and should further drive the move for patients to take more responsibility for their own health.