Cardiovascular disease (CVD) is still widely considered as a middle-aged man’s disease and this is clearly a misconception. In actual fact, CVD is the number one cause of death for women worldwide. Also, compared with men, women have a number of additional risk factors that are specific to them and should not be ignored by medical professionals. Laboratory testing has a key role to play in the diagnosis and follow up of women with CVD. CLI talked to Jean Onofrio, Senior Director, Global Assay Marketing, Siemens Healthcare Diagnostics, about this important health issue for women.

Q.What impact does cardiovascular disease have on women?
Cardiovascular disease, or CVD, is a significant health concern for women. In fact, it’s the number one killer of women globally, [1] and according to the World Health Organization (WHO), accounts for one-third of deaths in women. 

CVD also is the main cause of death for older women. Women generally develop CVD about 10 years later in life than men, likely due to the protective, anti-oxidant effects of estrogen prior to menopause.

Unfortunately, the misperception that CVD is a middle-aged man’s disease still persists. Understanding CVD’s global impact on women is one positive step toward battling the disease.

Q. What are the risk factors for CVD in women?  How do these compare to risk factors in men?
While many CVD risk factors, such as age, family history and high blood pressure, are similar in both genders, there are some, including diabetes, tobacco use and high triglyceride levels, that put women at higher risk. Other risk factors, like obesity and depression, are more prevalent in women. There are also some risk factors unique to women, including pregnancy complications, oral contraceptive use, hormone replacement therapy and polycystic ovary syndrome. It’s important for women to understand their CVD risk factors and discuss their concerns with their physician.

Q. How does the mortality rate of women with CVD compare to the mortality rate of CVD in men?
While the mortality rate is high for older women, a heart attack can occur at any age. For younger women, heart attacks are actually more deadly than for men.  According to the American Heart Association (AHA), among adults aged 45-62, women are twice as likely as men to die within the first year after a heart attack.

Also, more than twice as many women will develop heart failure within five years of surviving a heart attack compared to men, and three times more women than men will suffer a stroke after surviving a heart attack.

Q. What are some of the challenges associated with diagnosing CVD in women?
Women having a heart attack commonly present with symptoms other than chest pain, which makes diagnosis challenging. Rather, women often experience such less common symptoms as fatigue, indigestion, appetite loss and
“heart flutters.” 

Even though these symptoms may not be severe, they may still lead to deadly consequences. Unfortunately, many women, and often clinicians, disregard their symptoms, attributing them to other non-life-threatening conditions.

Adding to this challenge, women with CVD aren’t as likely as men to receive aggressive diagnosis and treatment. Consider that women receive only about 34 percent of interventional treatments, with and witout the placements of stents.

Q. What role does laboratory testing play in the diagnosis and management of women with CVD?  What about biomarkers?
CVD is largely preventable, and simple laboratory tests can help assess a person’s risk.

Laboratory professionals play an increasingly important role in providing access to both traditional and novel cardiac biomarkers that are available throughout the disease continuum. Also, whether conducted in the central lab or at the point-of-care, cardiac tests, such as high-sensitivity troponin, are key diagnosis tools.

By leveraging the appropriate use of laboratory diagnostic testing, clinicians can help enhance the assessment, diagnosis and follow-up care for women with CVD.

Reference
1.http://gamapserver.who.int/gho/interactive_charts/women_and_health/causes_death/ chart.html; accessed 11/27/12

It was over sixty years ago that Sir Richard Doll’s pioneering work first demonstrated a causal link between tobacco smoking and an increased risk of lung cancer. The lessons drawn from it have undoubtedly saved millions of lives over the years, but it is disappointing that according to the recently published European cancer mortality predictions for 2013, lung cancer remains the biggest cause of cancer death in male EU residents, and  is predicted to become the biggest cause of cancer mortality in women in the near future, overtaking deaths from breast cancer.
The trend is similar in the US. A recently published paper in the New England Medical Journal, which involved data from more than two million women at three different time periods, showed that women who smoke currently are at a far greater risk of death from lung cancer than were women who smoked in the 1960s and the 1980s; the risk is now equal for both genders. While other factors that increase the risk of lung cancer, such as asbestos and radon gas exposure, have now been identified, tobacco smoke is still thought to be responsible for around 90% of lung cancer cases.
During the decades since Doll’s work it has, of course, been demonstrated that the risk of death from many other diseases, including other cancers, ischemic heart disease, stroke, chronic obstructive pulmonary disease and asthma, is augmented by smoking tobacco. More recently it has been recognized that passive smoking can also increase the risk of smoking-related diseases, and that prenatal exposure to tobacco smoke increases the risk of low birth weight and premature neonates, as well as SIDS and asthma in infancy. But in spite of the concerted efforts that have been made to educate the public about the dangers of tobacco smoke over more than half a century, a substantial minority of the population, including many physicians, still smokes.
Now for the good news. Several comparative studies indicate that public smoking bans now operating in much of the developed world are already affecting the rate of cardiovascular and respiratory disease. And a very recent robust study from Belgium, giving data from the three phases of the ban in that country, where smoking was first prohibited in the workplace (2006), then in restaurants (2007) and finally in bars serving food (2010), demonstrates a fall in the premature birth rate after each phase. So finally at least those of us who have heeded the oft-repeated health message may benefit fully from our prudence!

Clinical decisions need to be made at the earliest possible time to facilitate the administration of quick and accurate treatment plans. Point of care testing (POCT) enables tests to be convenient and fast, making them suitable for use with a broad range of patients, including diabetics. Glycated hemoglobin (HbA1c) is commonly tested in diabetics as it provides a reliable measure of glycemic control (Figure 1). However, the role of HbA1c in the diagnosis of diabetes has only more recently been documented. HbA1c levels reflect average circulating glucose levels over the lifespan of red blood cells (2-3 months). Once hemoglobin molecules have been glycated, they become highly stable, enabling a greater level of clinical information to be obtained from them than a single glucose measurement taken at a particular point in time.

by Gavin Jones, Diabetes Product Manager, EKF Diagnostics

By taking serial HbA1c measurements, an individual’s control over their glucose levels can be assessed in response to changes in management strategies. Measurements should be taken every 2-6 months with target HbA1c levels set individually and therapy adjusted accordingly to provide the most effective treatment (1). The target ranges of HbA1c for diabetic patients, depending on their risk of severe hypoglycemia, cardiovascular status and co-morbidities, should be set between 6.5 – 7.5% DCCT (48 – 58 mmol/mol), with the non-diabetic reference range being 4.0 – 6.0% DCCT (20 – 42 mmol/mol). One point for consideration is that HbA1c results may be affected by any condition that leads to a change in red blood cell survival. But even then, HbA1c can be used to detect trends in a patient’s glycemic control.

HbA1c in POCT-based diabetes monitoring
HbA1c determination was originally based on methods such as ion exchange and affinity chromatography with alternative affinity and immunological methods following later, taking HbA1c into the POC environment.

Typically, when using laboratory-based testing, patients with existing diabetes are monitored for HbA1c every 2-6 months, requiring a visit to a nurse or phlebotomist and a follow-up appointment 1 to 2 weeks later to discuss the results. Use of POCT would mean that after just one visit, patients can leave with their results, eliminating the need for a follow-up appointment. By enabling an earlier therapeutic decision, diabetes control can be improved whilst also providing economic benefits in terms of cost and time.

Diabetes diagnosis
The benefits of HbA1c in the management of diabetes can also be directly applied to the diagnosis of diabetes. Unlike glucose levels, which are affected by what has been eaten and drunk in the previous 2-3 hours, the measurement of HbA1c levels does not require fasting. As a simple and immediate test for diabetes, POC HbA1c can support the early identification of at-risk individuals. This would rapidly enable them to make small changes to their lifestyle to significantly reduce the risk of developing type 2 diabetes.

Patients diagnosed with diabetes who are able to maintain low blood HbA1c levels also have a significantly reduced chance of complications after diagnosis (2); early detection by POCT can reduce this risk even further. The ability to rapidly assess and change these risk outcomes has significant health benefits and reduces the costs associated with recurrent leg ulcers, blindness, heart disease and stroke, for example, all of which are conditions and complications commonly associated with type 2 diabetes.

The World Health Organization (WHO) has recommended the use of HbA1c for the diagnosis of diabetes (3). In the UK for example, the National Institute for Clinical Excellence (NICE) has published guidelines for diabetes prevention which aim to identify people at high risk of type 2 diabetes and offer cost-effective, appropriate interventions to prevent or delay onset (4). Used in conjunction with a lifestyle health risk assessment, these guidelines advocate the monitoring of HbA1c levels to allow healthcare providers to  advise individuals on treatment regimens, depending on their classification as low, moderate or high risk. Current guidance, therefore, supports the use of HbA1c in screening for type 2 diabetes, and in the management of patients with diabetes. The use of POCT could improve the management of patients with established diabetes in both primary and secondary care settings and enable earlier type 2 diabetes diagnosis.

What to look for in a POC HbA1c analyser
Most POC HbA1c analysers use a single drop of blood (4-10 µL), which is applied to a reagent cartridge. The cartridge is then directly inserted into a desktop device for analysis. Time to results is generally between 3 to 10 minutes, depending on the analyzer. This quick turn-around time, in combination with simple operation, is key to maintaining effective POC testing.

Simplicity
To minimize human error and the subsequent need for repeat testing, a POC analyser should be as easy as possible to use. Also the analyser should be highly intuitive, requiring little user training. Features that support ease-of-use include ready-to-use reagent cartridges which can be inserted straight into the analyser. The blood sample can then be added directly, without the need for premixing or pipetting. Minimizing the number of steps in the procedure not only reduces the potential for user error, but also helps to standardize results by eliminating variation from different users.

Audit trails
For patient safety purposes, audit trails must be readily available. Use of barcode scanning for patient and user identification, as well as confirmation of the batch of reagents and controls used, ensures an analyser can provide such information in a timely manner. Two levels of quality controls that are recorded and held within the analyser’s memory are also ideal for auditing purposes.

Certification
Certification of the analyser in order to confirm delivery of accurate, standardized results should also be a key consideration. In an effort to standardize HbA1c results, the AACC set up the ’National Glycohemoglobin Standardization Program’ (NGSP) in 1996. In parallel, the International Federation of Clinical Chemistry (IFCC) developed reference methods for glycated hemoglobin. In 2006 and 2007, an international consensus between IFCC and AACC was agreed upon (5).

The calibration and certification of laboratories and manufacturers to the same standards has improved the conformity of results. However, in practice, differences can still be observed among technologies and between individual systems. These observed differences arise because of heterogeneity of hemoglobins, underlying differences in technologies (e.g. ion exchange, boronate affinity, immunoassay), calibration drifts or lot to lot variability. Providing the manufacturer follows the recommendations of the IFCC and NGSP to ensure instruments and reagents are accurately aligned and traceable to the reference method, this should not be a problem.

Methodology
There are POC HbA1c analysers available (e.g., the Quo-Lab, EKF Diagnostics, Cardiff, UK) (Figure 2) where results are not affected by hemoglobin variants (which do not result in reduced erythrocyte life span), labile glycated hemoglobin or hematocrit levels. Such analysers use Boronate Fluorescence Quenching Technology (BFQT) (6) (Figure 3) which is associated with simple, yet powerful multiple optical measurements. This is based on well-documented boronate affinity chromatography systems used in reference laboratories. However, as BFQT does not require chromatographic separation, the methodology allows for fast, simple and accurate POC measurement of HbA1c to deliver comparable results to chromatography-based techniques.

Summary
Type 2 diabetes can be managed easily and effectively through the monitoring of HbA1c levels, as opposed to blood glucose. POC diagnosis enables early detection in higher risk patients, before any additional complications arise. POCT therefore not only improves patient access to testing, but provides accurate diagnoses there and then. Treatment strategies can be determined immediately, eliminating the need for a follow-up visit to discuss the results. The ability for diagnosis to occur near to the patient provides greater convenience, thus increasing the likelihood of compliance.

When selecting an analyser for use at the POC, users need to bear in mind that it needs to be a convenient and appropriate option. The focus should be on meeting regulatory requirements, as well as ease of use in order to ensure rapid testing, with accurate, standardized resulting data.

References:
1. Diabetes UK. HbA1c Standardization: Information for Clinical Healthcare Professionals. 2009. http://www.diabetes.org.uk/Guide-to-diabetes/Monitoring/Blood_glucose/Glycated_haemoglobin_HbA1c_and_fructosamine/HbA1c_Standardisation_Information_for_Clinical_Healthcare_Professional.
2. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86.
3. World Health Organization. Use of glycated hemoglobin (HbA1c) in the diagnosis of diabetes mellitus. 2011. www.who.int/diabetes/publications/report-hba1c_2011.pdf.
4. National Institute for Health and Clinical Excellence. Preventing type 2 diabetes: risk identification and interventions for individuals at high risk. 2012. www.nice.org.uk/nicemedia/live/13791/59951/59951.pdf.
5. Geistanger A, Arends S, Berding C, Hoshino T, Jeppsson JO, Little R, Siebelder C, Weykamp C; on behalf of the IFCC Working Group on Standardization of Hemoglobin A1c. Statistical Methods for Monitoring the Relationship between the IFCC Reference Measurement Procedure for Hemoglobin A1c and the Designated Comparison Methods in the United States, Japan, and Sweden. Clin Chem. 2008 Aug;54(8):1379-85.
6. Wilson DH, Bogacz JP, Forsythe CM, Turk PJ, Lane TL, Gates RC and Brandt DR. Fully automated assay of glycohemoglobin with the Abbott IMx analyzer: novel approaches for separation and detection. Clinical Chemistry October 1993 vol. 39 no. 10 2090-2097