Declining heart attack severity drives drop in CHD deaths

Medical Tribune March 2009 P1
David Brill

A decrease in the severity of heart attacks is fuelling the decline in coronary heart disease (CHD) deaths in the US, new research suggests.

The study – an analysis of 10,285 myocardial infarction (MI) cases hospitalized over 15 years – showed significant declines across almost all indicators of severity.

This trend, which appears to be mirrored by data from some parts of Asia, was independent of either gender or ethnicity.

“This landmark study suggests that better prevention and better management in the hospital have contributed to the reduction in deaths,” said Dr. Merle Myerson, principal investigator of the Atherosclerosis Risk in Communities (ARIC) study, published in Circulation. [2009 Jan 19; Epub ahead of print]

“Better control of risk factors for heart disease, such as blood pressure and cholesterol, as well as improvements in hospital management, may lessen the severity if somebody has a heart attack,” he said.

The time between symptom onset and arrival at hospital remained constant throughout the study, period with only around a third of patients arriving at the hospital within 2 hours of an attack.

Dr. Adrian Low, a consultant at the National University Heart Centre Singapore, stressed the importance of raising public awareness in order to further improve MI outcomes.

“While this study is reassuring, it also emphasizes that we still have room for improvement. A significant percentage of patients still present late to us for treatment,” he said.

“We know that early presentation and appropriate management can result in better outcomes. This will only be achieved with enhanced public education and a better evaluation of how we can overcome our shortcomings,” he added.

The ARIC investigators reviewed MI discharge data from 1987 to 2002, taken from hospitals across four communities in North Carolina, Maryland, Mississippi and Minnesota. The analysis was limited to white and African-American patients, aged 35 to 74.

Previous studies had shown that CHD mortality in the US was dropping but that the incidence of MI remained unchanged – prompting the researchers to investigate whether declining MI severity might be the driving force behind the bigger-picture CHD effect.

In-hospital deaths from acute MI in Singapore have also dropped over a similar period, according to data from the National Heart Center, where overall inpatient mortality declined from 20.6 percent in 1988 to 14.7 percent in 2002. [Ann Acad Med Singapore 2007 Dec;36(12):974-9] A study published last year by the Singapore’s National University Hospital, meanwhile, showed that the use of evidence-based medications for MI has significantly reduced 1-year mortality in both elderly and young patients. [Am J Geriatr Cardiol 2008 Jan-Feb;17(1):21-6]

Low added that the ARIC study “reinforces our current understanding that cardiovascular risk factors, treated aggressively, can impact on subsequent development and outcome of acute MI,” but noted that there are several limitations to the research. The generalizability to other populations is not clear, nor is it known which specific measures led to the improved outcomes, he said. He also added that some of the severity indicators used by the researchers are proxies for disease severity, while more direct measures such as left ventricular ejection fraction were unavailable.

Twenty MI severity indicators were used in the ARIC study, including the proportion of cases having major ECG abnormalities. For ST-segment elevation, for example, the proportion of cases dropped by 1.9 percent per year (P = 0.002), while the percentage of cases with any major Q wave dropped by 4.5 percent per year (P<0.001).>

Greater awareness needed on childhood anxiety disorders

Medical Tribune March 2009 P5
David Brill

Pediatric anxiety disorders are “under-recognized and under-treated” and could be contributing to depression, drug abuse and educational underachievement in later life, a leading US psychiatrist has warned.

As many as 20 percent of children have some sort of anxiety problem but few are likely to be receiving optimal therapy, Professor Graham Emslie wrote in a recent New England Journal of Medicine editorial. [2008 Dec 25;359(26):2835-6]

Specialists at KK Women’s and Children’s Hospital (KKH) in Singapore, where referrals for pediatric anxiety disorders are low but rising, agreed that the problem is under-recognized and called for greater awareness among medical practitioners.

Emslie, a professor of psychiatry and pediatrics at the University of Texas Southwestern Medical Center, said that children often develop avoidance or coping strategies which can mask the true extent of the problem and contribute to the diagnosis being missed. Genuine anxiety disorders may also be dismissed as “normal, developmentally appropriate worries, fears and shyness,” he said.

The success of the CAMS* study, published in the same edition of the journal, highlights that the treatment options for pediatric anxiety are now more effective than ever before, Emslie said. The researchers found that 81 percent of children showed significant improvements in their anxiety levels when cognitive behavioral therapy (CBT) was combined with the selective serotonin-reuptake inhibitor sertraline. [N Engl J Med 2008 Dec 25;359(26):2753-66]

CBT is typically employed as the first line treatment at KKH but may also be combined with medications in severe cases, according to principal psychologist Ms. Frances Yeo. The number of children with anxiety disorders seen at the hospital rose from 26 in 2007 to 48 in 2008.

Yeo noted that the under-recognition of pediatric anxiety disorders may result from children’s inability to vocalize their worries and fears, which may subsequently manifest themselves as behavioral problems and lead to the child being wrongly labeled as lazy or difficult.

“Children usually show signs of their anxiety through physical symptoms such as stomachaches, headaches, hyperventilation, heart palpitations and tightness in the chest. These symptoms are rather vague and can overlap with many other disorders which make it difficult to distinguish,” she added.

“The first step for the medical community is awareness. GPs need to be alert for children with vague physical symptoms which cannot be explained by medical illnesses,” she said.

Pediatric anxiety disorders comprise a spectrum of conditions including social phobias, separation anxiety disorder, and generalized anxiety disorder. Children who are affected at ages 14 – 16 are more likely to have poor educational, mental health and social role outcomes at ages 16 – 21, a study of 1,265 New Zealand adolescents showed. [J Am Acad Child Adolesc Psychiatry 2001 Sep;40(9):1086-93]

Emslie noted that the exposure component seems to be the most effective part of CBT for children with avoidance strategies, suggesting that they should be encouraged to tackle their phobias head on. Doctors have an important role to play in this, he said, adding that they can unwittingly “collude” with avoidance coping by writing medical notes which give anxious children an excuse to miss school.

Dr. Ng Koon Hock, visiting consultant psychiatrist to the Mental Wellness Service at KKH, said that parents may be failing to recognize anxiety disorders because they tend to downplay a child’s emotions and focus overly on their behavior as a disciplinary issue. “There is less tendency to look at things from the child’s perspective,” he said.

Ng believes that doctors are generally reluctant to liberally grant medical leave to children who regularly makes suspicious-looking health complaints, but noted that this can be a difficult balancing act.

“If the child is very stressed and wants to escape from the problem then in the long-term it’s not helpful, but sometimes it does allow them to get by in the short term,” he said.

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*CAMS: Child-Adolescent Anxiety Multimodal Study

FDA warns on skin anesthetic dangers

Medical Tribune March 2009 P6
David Brill

The US FDA has issued a new public alert on skin-numbing drugs, warning of “potentially serious and life-threatening” consequences if products are misused.

Absorption of topical anesthetics from the skin to the bloodstream can cause seizures, arrhythmias, coma and even death, the organization said in a recent news release.

The warning specifically highlights creams, gels and ointments containing lidocaine, prilocaine, tetracaine and benzocaine – products which are available over the counter or by prescription in the US. These are often used in cosmetic and medical procedures, as well as for general relief of pain and itching.

Two women, aged 22 and 25, are already reported to have died in the US from using skin anesthetics prior to laser hair removal. They wrapped their legs in plastic to increase the pain-relieving effects of the creams but developed seizures and died from the toxic effects, the FDA said in a 2007 statement, which first warned about the use of these products.

Consumers should avoid heavy usage across large areas of skin, select products with the lowest possible amount of anesthetic, and avoid applying to broken or irritated skin, the latest warning advises. They are also advised to refrain from wrapping recently-treated skin in plastic or applying heating pads to the area.

Healthcare professionals, meanwhile, “should determine whether adequate pain relief can be safely achieved with a topical anesthetic, or whether a different treatment would be more appropriate,” the health advisory adds.

Dr. Melvin Ee, a consultant dermatologist at the National Skin Centre, Singapore, stressed that the adverse events highlighted by the FDA are rare but said that the warning serves as a timely reminder of the increasing use of skin numbing products in cosmetic and aesthetic procedures.

“I think the warning is important but the context must be taken into consideration,” he said.

“Topical anesthetics within the hospitals are prescribable medications and it is the onus of the prescribing doctor to adhere to safe prescribing. I personally think that if a doctor adheres to safe prescribing and according to the formulary of the medication, these are useful and safe drugs to use. The public should be made aware of the possible side effects of the medication but it must not be sensationalized.”

Ee advised physicians to consider the suitability of a patient’s age and check for allergies, potential interactions with any other medications, and a history of blood disorders or G6PD deficiency before using the products. They should also look for breaks in the skin and assess the required dosage.

Topical anesthetics reduce painful sensations by interfering with sodium and potassium currents in neuronal membranes, thereby preventing depolarization and inhibiting transmission of the signal. Excessive levels in the bloodstream can lead to systemic toxicity, the effects of which are usually manifested through the central nervous and cardiovascular systems.

Ee added, however, that this is outcome is rare and likely only to happen in the context of an overdose. The more common side effects tend to include transient local reactions at the application site, such as edema, paleness, erythema and a mild burning sensation, he said. In very rare circumstances – less than 0.1 percent of cases – application of topical anesthetics in children can result in allergic reactions leading to shock and methemoglobinemia, he added.

The FDA also expressed concerns over a recent trial which reported that lidocaine gel reduced discomfort and improved patient satisfaction when applied ahead of mammography screening. Despite these positive findings and a lack of adverse events there is potential for harm if the technique becomes used more widely, the FDA said, acknowledging the relatively small size of the 418-women study. [Radiology 2008 Sep;248(3):765-72]

Simple surgical checklist cuts deaths and complications

Medical Tribune March 2009 P7
David Brill

Using a simple checklist for surgical procedures could dramatically reduce mortality and complication rates across the globe, the “unprecedented” results of a new study show.

Implementation of the WHO-developed list saw post-surgical death rates drop from 1.5 percent to 0.8 percent (P=0.003), and inpatient complications fall from 11 percent to 7 percent (P<0.001)> over 11 months.

The checklist was trialed at hospitals in eight diverse cities, ranging from London to Manila to Ifakara in Tanzania. Data were collected from 3,733 procedures conducted before implementation of the list, and 3,955 after. [N Engl J Med 2009 Jan 29;360(5):491-9]

“The concept of using a brief but comprehensive checklist is surprisingly new to us in surgery. Not everyone on the operating teams was happy to try it,” said Dr. Atul Gawande, senior author of the study. “But the results were unprecedented. And the teams became strong supporters.

“These findings have implications beyond surgery, suggesting that checklists could increase the safety and reliability of care in numerous medical fields. The checklists must be short, extremely simple, and carefully tested in the real world. But in specialties ranging from cardiac care to pediatric care, they could become as essential in daily medicine as the stethoscope,” added Gawande, an associate professor of surgery at Harvard Medical School, US, and team leader for the WHO project.

The checklist was first launched in 2008 as part of new “safe surgery” guidelines from the WHO. It comprises 19 items, and is used at three “critical junctures” in care: before anesthesia, before incision, and before the patient is taken from the operating room.

Rates of surgical site infection also dropped following implementation of the list – from 6.2 to 3.4 percent (P<0.001)> – and unplanned reoperation rates decreased from 2.4 to 1.8 percent (P=0.047).

Dr. Sophia Ang, patient safety officer and associate chairman of the medical board at National University Hospital (NUH), Singapore, said that similar checklists are already in use at NUH.

“Some of these have been in place for a long time, such as an instrument count, sponge count and needle count,” she said.

“There is no deliberate effort on our part to do this as a scientific research so we have no findings to conclusively show that the changes have brought about improved outcomes. Some of the elements were introduced in phases and over time and we are continually reviewing and improving on them to enable us to meet our patient safety needs,” she added.

Some 234 million operations are performed worldwide each year, according to Gawande and his colleagues. At least half of all complications arising from surgery are thought to be avoidable, they add.

The study, which was conducted between October 2007 and September 2008, included only patients aged over 16 who underwent noncardiac surgery. The other cities where the checklist was tested were New Delhi, India; Toronto, Canada; Amman, Jordan; Auckland, New Zealand; and Seattle, US.

Everolimus shows promise for advanced stomach cancer treatment

Medical Tribune March 2009 P9
David Brill

Everolimus could provide a viable new treatment option for advanced gastric cancer, Japanese investigators said recently, following the conclusion of a phase II trial of the drug.

After 8 weeks of therapy everolimus halted tumor growth in 55 percent of patients, with 45 percent showing signs of tumor shrinkage.

A phase III trial involving some 500 patients will open for enrollment later this year, the drug’s manufacturer, Novartis, announced following the presentation of the new data at an American Society of Clinical Oncology symposium in January.

The multicenter, open-label study involved 54 Japanese patients of Asian descent who had previously undergone heavy treatment with chemotherapy.

"There are very limited treatment options for patients who progressed despite the standard treatment for this aggressive cancer," said lead researcher Dr. Atsushi Ohtsu, director of the Research Center for Innovative Oncology at the National Cancer Center Hospital East, Chiba, Japan. "The results from this study demonstrate that [everolimus] has the potential to provide an effective new option for these patients."

Patients in the study took 10 mg oral everolimus daily for an average of 57 days. The overall rate of adverse events – including anorexia, vomiting and stomatitis – was around 10 percent, with serious adverse events occurring in some 3 percent.

The median progression-free survival with everolimus was 83 days. At 4 months, around 30 percent of patients were still progression-free.

Everolimus inhibits the mammalian target of rapamycin (mTOR) – a cell signaling protein which is implicated in the development of several cancers. The drug has already shown promise for advanced renal cancer carcinoma and is currently under regulatory review in Europe and the US for this indication. A phase III randomized controlled trial, published last year, found that the drug prolonged progression-free survival by a median of 2.1 months over placebo in patients with metastatic renal cell carcinoma. [Lancet 2008 Aug 9;372(9637):449-56]

Gastric cancer is the most common type of cancer in East Asia, accounting for 18.9 percent of new cases in 2007, according to data from the American Cancer Society. Globally, it is the second leading cancer and is responsible for some 866,000 deaths worldwide each year, according to the WHO.

The risk of gastric cancer is thought to be increased by eating a diet high in salted, pickled and smoked foods, and by long-term infection with Helicobacter pylori. Male gender, smoking and age above 50 are also important risk factors.

Preventive antibiotics cut ICU death rates

Medical Tribune March 2009 P10
David Brill

Adopting a widespread preemptive approach with antibiotics could save lives in the Intensive Care Unit (ICU), Dutch researchers have recently reported.

Absolute mortality at 28 days was reduced by 3.5 percent in patients who received intravenous cefotaxime along with a cocktail of antibiotics applied topically to the stomach and orophyarynx. A simpler regimen – applying antibiotics only to the oropharynx – reduced mortality by 2.9 percent, as compared with standard care.

The findings are likely to prove contentious in the era of rising antibiotic resistance rates and hospital-associated infections. A Singapore infectious disease expert, who recently called for tighter regulation of the nation’s antibiotic usage, said that a similar approach could be adopted here but expressed his concern that resistance levels would increase in the long term.

The study, conducted across 13 ICUs in the Netherlands, randomized 5,939 patients to standard care or one of the two antibiotic regimens. Patients were only eligible if they were expected to be intubated for more than 48 hours or to remain in the ICU for more than 72 hours. [N Engl J Med 2009 Jan 1;360(1):20-31]

Lead researcher Dr. Anne Marie de Smet, of the University Medical Center Utrecht, said that the trial demonstrates that the benefits of preventive antibiotics outweigh the disadvantages.

“There are very few interventions in the ICU which can lower mortality on their own. These are not patients who come in for surgery and leave the next day – these people are really ill,” she said.

Antibiotic resistance rates did not rise significantly over the course of the 6-month study but longer follow-up data are needed, said de Smet. She added that The Netherlands has unusually low rates of resistance due to its strict regulations on antibiotic usage.

Dr. Hsu Li Yang, an infectious disease consultant at National University Hospital, Singapore, said that he would be “very concerned that resistance rates would increase” were the strategy to be adopted here, but added that is “for society as a whole to decide” whether such a move would be beneficial given the obvious short-term advantages.

“Doctors should not ‘allow’ patients to die so that future patients may be better or more easily treated. What we try to do is to retard the rise of resistance while preventing any increased mortality that may arise from inadequate use of antibiotics … minimize the use of antibiotics for those who do not need them and prescribe appropriate but not excessive antibiotics for those patients who do,” he said.

“Similar strategies might be adopted [here] in the future following the results of this study,” said Hsu, adding that the trial was very well conducted and one of the few in this field with adequate statistical power to demonstrate a significant mortality reduction.

The researchers used an antibiotic paste containing colistin, tobramycin and amphotericin B for both strategies. In the more comprehensive approach – selective digestive tract decontamination – the paste was applied topically to the stomach and oropharynx, and intravenous cefotaxime was given for the first 4 days. In the simpler strategy – selective orophyarygeal decontamination – the paste was just applied to the oropharynx.

Hsu added that that a different combination of antimicrobial agents would probably be necessary were the approach to be adopted in Singapore hospitals, where resistance rates are considerably higher than in the Netherlands.

Hsu recently co-authored a position paper calling for more data to be gathered on the use of antibiotics in Singapore and for the Ministry of Health to take a greater role in regulating usage. [Singapore Med J 2008 Oct;49(10):749-55]

Lifestyle program boosts diabetes control in overweight Chinese

Medical Tribune March 2009 SFV
David Brill

An integrated lifestyle intervention program, including dietary supplements and meal replacements, can help overweight Chinese diabetics lose weight and improve glycemic control, a new study has shown.

Patients who followed the program for 24 weeks lost an average of 2.7 kg and saw their HbA1c drop by 0.8 percent compared to baseline (P<0.001).>

Such were the benefits of the intervention that 15 of the 100 type 2 diabetics who followed it had had their diabetes medication dosages reduced by the end of the trial, while a further seven stopped taking them altogether.

The results of the study, led by Dr. Jianqin Sun of Fudan University, Shanghai, were announced at a recent Singapore press conference and published in the Asia Pacific Journal of Clinical Nutrition. [2008; 17(3):514-24]

The intervention program included diabetes education, nutritional counseling, meal replacement with dietary supplements, and weekly progress reports with a physician and a dietician. It was compared in a randomized prospective trial against a simpler intervention comprising only education on diet and physical activity. Fifty patients were included in this reference group.

Professor William Garvey, a US diabetes expert who commented on the study, described the reduction in HbA1c as “very impressive” given that the intervention patients were already well-controlled, with an average HbA1c of 7.1 percent at baseline. He also noted that the potential to reduce or stop medications provides a good incentive for diabetic patients to lose weight, but stressed that these adjustments should only be made following proper consultation with a physician.

Dr. Kevin Tan, vice-president of the Diabetic Society of Singapore, said that the study demonstrates the viability of meal supplements as a therapy for diabetes, adding that this option should be explored for all patients who are overweight.

“Meal supplements or replacements have not been talked about much so a lot of doctors don’t think about them, but they do play a part in diabetes management in terms of helping to reduce calorie intake and helping patients to lose weight. If GPs realize that this can be part of their usual holistic diabetes care, along with the medications, exercise and weight control, then I think it will help to improve sugar control in their diabetic patients,” he said.

Participants in the study were all type 2 diabetics aged 18 to 70 with a BMI of 23 kg/m2 or above. The lifestyle intervention also significantly improved blood pressure (BP), with patients in this group recording average reductions of 7.5 mmHg for systolic BP and 3.4 mmHg for diastolic BP, at 24 weeks as compared to baseline. These reductions were significantly greater for the intervention group compared to the reference group.

The waist-to-hip ratio was also reduced among patients in the intervention group compared to those in the reference group.

“Dietary supplements are not the magic answer for everybody but they can be helpful in many patients,” said Garvey, who is based at the University of Alabama at Birmingham, US.

“If you have a patient who needs to lose weight and you feel that they need more structure in terms of their dietary plan – less guesswork and more clear-cut guidance in terms of what the diet will be from day to day – a meal replacement is a really good tool to use,” he said.

Garvey acknowledged that the short duration of the trial makes it hard to assess the long-term sustainability of the intervention, but added that the structured nature of the program teaches important behavioral modification skills which continue to be applicable beyond the trial setting.

The burden of type 2 diabetes in China is increasing rapidly, according to the study authors, who note that the prevalence among large city residents rose from 4.6 percent in 1995 to 6.4 percent in 2002. In Singapore the burden could be even higher, with data from the 2004 National Health Survey suggesting a diabetes prevalence of 8.2 percent among residents aged 18 to 69.

The trial by Sun et al. was funded by Abbott Laboratories, which manufactures the dietary supplement used in the study.

Nuisance bleeding prompts patients to drop clopidogrel

Medical Tribune March 2009 P18

David Brill

“Nuisance bleeding” is a common and under-recognized cause of clopidogrel cessation following drug-eluting stent implantation, according to a recent study.

Some eleven percent of patients who experienced nuisance bleeds stopped taking the drug, increasing their long-term risk of potentially fatal stent thrombosis, US investigators reported.

The American Journal of Cardiology study is the first to quantify the impact of superficial bleeding on clopidogrel compliance, the authors claim, noting that previous research has tended to focus on major and internal bleeding events. Nuisance bleeding included bleeds from minor cuts, easy bruising, ecchymosis and petechia. [2008 Dec 15;102(12):1614-7]

Dr. Ron Waksman, the study’s lead author, said that he was “alarmed” by the findings and called for better education of patients about the potential complications of prolonged antiplatelet therapy.

“Patients should be aware that they are going to experience this bleeding and that they should still adhere to the clopidogrel. We have to explain to them that having stent thrombosis could be life-threatening whereas nuisance bleeding is just a nuisance,” he said.

“This is one of the taxes that you pay if you get a drug-eluting stent. It’s something that is not usually captured in clinical trials so we don’t tend to care much about it but for patients it is a real issue,” he added.

Waksman and his colleagues followed up 2,360 patients who underwent successful sirolimus-eluting stent implantation at Washington Hospital Center (WHC), a tertiary referral hospital in the US, and were subsequently recommended for a minimum of 6 months of dual antiplatelet therapy.

After 36 months of clinical follow-up, 32.4 percent of patients had experienced some form of bleeding – 85.7 percent of which fell into the nuisance category. Of those who had nuisance bleeds, 11.1 percent stopped taking clopidogrel and 5 percent stopped taking aspirin.

Around 70 percent of those who experienced nuisance bleeds did so on a daily basis, according to Waksman, who is associate director of the division of cardiology at the WHC. He noted that the aspirin dosage can be reduced for those who continue to experience inconvenient bleeding but stressed that clopidogrel should be maintained for at least a year.

Future research is directed at better understanding the mechanisms by which these drugs affect platelet inhibition, said Waksman, adding that this will help us to learn why some patients experience bleeding while others do not.

“It can go both ways: those who don’t bleed at all may be still at risk for stent thrombosis and may need a higher dose, while those who have nuisance bleeding may be too sensitive to the drug and could do well with half the dose,” he said.

Action needed on S. aureus in developing SE Asian countries

Medical Tribune March 2009 P12

David Brill

The burden of Staphylococcus aureus in low-income south and east Asian countries is poorly understood and could pose a threat to the health of both developed and developing countries, an international team of researchers has warned.

The lack of data on drug resistance rates in particular could exacerbate the problem if a strategic research program is not defined, the group wrote in a recent review in The Lancet Infectious Diseases. [2009 Feb;9(2):130-135]

The regional prevalence of methicillin-resistant S. aureus (MRSA), for example, remains largely unknown, although surveillance data from India and China suggest that the strain represents a substantial and rising proportion of the overall S. aureus burden. This knowledge gap could be contributing to the lack of recognition given to the problem by healthcare workers and the public, the study authors say.

The unregulated sale of cheap, substandard over-the-counter antibiotics could also be fuelling the emergence of MRSA in these countries, they add.

Mortality data on S. aureus in developing Asian countries are also scarce, but one study from a Thai hospital found that the death rate from bacteremia could be as high as 48 percent. [Lancet Infect Dis 2006 Feb;6(2):70-1] A comparable study in the US reported a mortality of just 22 percent. [Arch Intern Med 2003 Sep 22;163(17):2066-72]

Children seem particularly vulnerable to S. aureus in low-income countries in south and east Asia, unlike in high-income countries where the incidence of the bug appears largely to increase with age. The same study from Thailand found that S. aureus infections were most common in neonates, who made up 25 percent of all cases, while another study from Laos demonstrated that S. aureus was the number one cause of bacteremia in children aged under 1 year. [Am J Trop Med Hyg 2006 Nov;75(5):978-85]

“The burden of S. aureus disease in developing regions is inadequately appreciated or understood. An initiative is needed to raise the profile of S. aureus disease in developing countries, and to fund studies to better define the healthcare challenges and potential practical solutions relating to this important global pathogen,” wrote the authors, who hail from the Mahidol University in Bangkok, Thailand, the University of Oxford, UK, and the University of Washington in Seattle, US.

A total of 96 papers were included in the literature review – comprising published data from 20 low-income or lower-middle income countries including Indonesia, the Philippines, Vietnam and Cambodia.

Besides establishing the prevalence of MRSA, future research should also be directed at identifying risk factors for S. aureus and implementing cheap but effective mechanisms for infection control, the authors wrote.

Chronic kidney disease in primary care: Time to embrace GFR

Medical Tribune March 2009 P15

Chronic kidney disease (CKD) encompasses a wide spectrum of disorders ranging from minor urinary abnormalities to end stage kidney failure. The prevalence of CKD worldwide is thought to be increasing, largely due to the rising incidence of diabetes and the rapid aging of the population.

March 12 is World Kidney Day. The message of raising awareness is particularly pertinent for primary care physicians (PCPs), who will increasingly encounter patients with CKD in its various stages. It is important, therefore, for them to know how to diagnose and manage CKD, and when to refer patients to a nephrologist.

Diagnosis

It is crucial to diagnose CKD as early as possible since complications can ensue if a referral is delayed. Indeed, most patients with CKD will die of cardiovascular disease before developing end stage kidney failure, so management of these risks by their PCP will improve outcomes. Screening of at-risk individuals is thus critical and physicians should adopt a proactive approach, as outlined in the guidelines. Diabetes is the commonest cause of CKD but a high index of suspicion should also be retained in patients with hypertension, over-50s, smokers, the obese, and those with a family history of CKD.

The diagnosis and classification of CKD should be based on a patient’s kidney function, as estimated by glomerular filtration rate (GFR) and the presence of other evidence of chronic kidney damage. These guidelines, which have been widely adopted worldwide, recognize five stages of kidney disease (Table 1).

Contrary to popular perception, a diagnosis of CKD does not routinely require 24-hour urine measurements or expensive radionuclide studies and can usually be made using three simple tests available to every PCP: serum creatinine (SCr), urine protein measurement using an early morning specimen, and urine microscopy. GFR can then be estimated by putting the patient’s data into easy-to-use mathematical formulae, which have been derived from large population studies. The 4-variable Modification of Diet in Renal Disease (MDRD) formula has widespread applicability and is currently the most commonly used formula in routine practice worldwide. Physicians can also estimate GFR using the internet: type “MDRD GFR calculator” into the search engine and input the patient’s values to calculate the estimated GFR (eGFR).

Many laboratories worldwide are already using these formulae to report eGFR but their adoption has been slower in Asia, where some nephrologists have questioned their applicability to local patients. The MDRD formula, for example, has not been validated in an Asian population, although a modified version is currently being explored in Chinese patients. Our division at National University Hospital (NUH) is also devising a Singapore-specific formula.

We should not, however, be paralyzed into inactivity while we await these new formulae. It is time to move on from the notion that 24-hour urine testing is the cornerstone of CKD diagnosis and begin routinely reporting eGFR along with SCr. It is not only easy to calculate but also more convenient for both PCPs and patients – negating the laborious and inaccurate process of collecting and labeling samples. The existing GFR formulae have limitations but they nonetheless provide a long-term view of kidney function in an individual patient, enabling CKD progression to be tracked over time. A reduction in eGFR exceeding a certain range can provide a warning sign, prompting PCPs to make an early referral to a nephrologist.

Twenty-four hour urine collection still has a place in diagnosing CKD, but should be used to further evaluate an abnormal eGFR or proteinuria rather than as a first-line diagnostic tool. Urine examination can identify protein and red cells and casts, giving further information as to the cause of CKD. Additional radiological tests are only required for further evaluation and/or in those with clinical symptoms or signs of CKD.

In evaluating patients with newly-diagnosed stage 3 to 5 CKD, clinicians should obtain previous measurements of SCr and eGFR to assess the rate of progression to date. A blood test showing an eGFR below 60 mL/min/1.73 m2 in a patient without established CKD should prompt:
· Clinical assessment for underlying conditions such as sepsis, heart failure or hypovolemia
· Clinical examination for bladder or prostate enlargement
· A review of medications, particularly non-steroidal anti-inflammatory drugs and traditional medications
· Urinalysis: haematuria and proteinuria suggest the possibility of glomerulonephritis, which may be rapidly progressive
· Repeat SCr, eGFR and potassium measurement within a maximum of 5 days

If acute kidney failure is suspected, the patient should be referred to a nephrologist. Patients with stable CKD should be followed up according to their eGFR (Table 1).

Practice Guidelines

Guidance on the diagnosis and management of CKD is available from several international sources. The guidelines from the UK Renal Association are particularly simple to follow and contain useful treatment algorithms. Helpful guidelines are also available from the US National Kidney Foundation, the Canadian Society of Nephrology, and CARI (Caring for Australasians with Renal Impairment).

Treatment

The vast majority of CKD patients being managed by PCPs will be in stages 1 and 2, but patients with early stage 3 CKD will also represent a significant proportion. Stage 3 patients who progress or are proving difficult to manage in primary care, and stage 4 and 5 patients, should be referred to nephrologists.

All CKD patients should be advised on diet and lifestyle modification as appropriate. Lipid-lowering therapy should be considered for all patients and aspirin for those at high cardiovascular risk. Meticulous control of hypertension is extremely important in CKD and most patients will need more than two drugs to achieve optimal control. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should be given to all patients with proteinuria, diabetic patients with microalbuminuria, and patients with heart failure but combinations of these two drugs should only be initiated under specialist supervision.

Physicians should refer to the guidelines for further advice on the thresholds for initiating and maintaining antihypertensive treatment, and for who, when and how to refer. They should also familiarize themselves with the indications for early referral to a nephrologist. The need for a prompt referral is particularly pressing in acute kidney failure, as this requires emergency treatment.

Disease management tools

Partnerships with nephrologists play a crucial role in helping PCPs to recognize the variability in CKD progression and to treat each patient individually. At NUH and National Healthcare Group in Singapore we are developing a ”Right-Siting” program for patients with early CKD so that they can be managed and tracked to optimize outcomes. The initiative is still in the planning stages but is due to launch in the coming months. We hope that this program will give PCPs greater knowledge and confidence with managing CKD, facilitate referrals, and provide patients with greater continuity of care and a more holistic approach to their management.

Conclusion

Our understanding of CKD has come a long way in recent years and it is important for physicians to familiarize themselves with the latest guidelines. The use of GFR in particular should be embraced, and patients should be classified into the 5 stages of CKD to enable appropriate referrals. Forging closer ties with nephrologists will help PCPs to tackle the ever-increasing burden of CKD and improve quality of care and outcomes for patients.

Integrity and objectivity on trial: Rebuilding confidence

Medical Tribune March 2009 P16

The ongoing fallout from the withdrawal of rofecoxib in 2004 continues to expose the core values of the international research community to debate. In the second of a two part series, David Brill looks at the safeguards being put in place to prevent it from happening again, and finds out how Southeast Asia can play its part in helping to restore the damaged reputation of medical research.


When the integrity of medical science is threatened, “patients, clinicians and researchers are all at risk of harm, and public trust in research is jeopardized,” wrote the editors of the Journal of the American Medical Association in an editorial last year. “Ensuring, maintaining, and strengthening the integrity of medical science must be a priority for everyone,” they concluded. [JAMA 2008; 299(15):1833-1835]

The trigger for this call to action was the publication of two new papers shining yet more light into the uncomfortable darkness surrounding the withdrawal of rofecoxib. With every painful new insight revealed by the ongoing litigation process – these latest revelations alleged the ghostwriting of manuscripts and the questionable presentation of mortality data in key clinical trials – the restoration of this integrity seems an ever-more distant target. [JAMA 2008;299(15):1800-12; JAMA 2008;299(15):1813-7]

The task is one that faces the entire medical profession, but for Professor Jeffrey Drazen, editor-in-chief of the New England Journal of Medicine (NEJM), it has taken on a particularly personal significance. The journal became an unwitting accomplice in the rofecoxib affair when it published the Vioxx Gastrointestinal Outcomes Research (VIGOR) study – later to be tainted for its omission of three late-breaking myocardial infarctions. [N Engl J Med 2000;343:1520-8; N Engl J Med;2005 353:2813-4] The saga, he says, has “changed the rules” for medical journal editors.

The NEJM, for its part, is fighting on several fronts to ensure the objectivity of the research contained within its pages. Along with other major medical publications, the journal now stipulates that clinical trials be registered in an international database – a requirement which prevents the changing of protocols mid-trial and creates an internationally-harmonized norm, Drazen says. The editors have also learned to demand personal accountability for the data, request longer adverse event reporting, and be more aggressive about querying authors when they feel that there are discrepancies, he adds.

Drazen believes, however, that the long-term solution to the rebuilding process lies out of the hands of the journals and at the very heart of medical research training. “People need to understand that you’re not here to make the boss happy – you want to report the truth,” he says. “In all research we need to teach this culture that [focuses on] getting it right, not just getting it published. Publishing papers is a way to gain fame and reputation, but if you publish a lot of papers that are wrong you’ll start off on a high but you’ll crash.”

The damage to the reputation of medical research has perhaps been most keenly felt in the US, but for Southeast Asia the stakes are equally high. As the region continues to promote itself as a biomedical research hub, financial and commercial interests in its countries grow, and the potential for disaster increases. And with the shadow of Dr. Hwang Woo Suk, the discredited South Korean stem cell scientist, still looming large, the need for adequate ethical safeguards in the region is beyond question.

Singapore, for one, appears already to be taking action to ensure the future integrity of its research. Ethics feature prominently in the nation’s Good Clinical Practice (GCP) Guidelines, a cornerstone of all research conducted in the country, and are also moving up the agenda at the Yong Loo Lin School of Medicine, which in September 2006 became the first medical school in Southeast Asia to open a dedicated academic center for biomedical ethics. At the national level, approval for clinical trials must be gained from the Health Sciences Authority, which scrutinizes all proposals before granting the required certificate.

Much of the responsibility for protecting the integrity of research, however, still lies at the doorsteps of the individual centers and their institutional review boards. Professor Fong Kok Yong’s role, as chairman of division research, is to promote and encourage research at Singapore General Hospital (SGH) – just one of several research centers in the country which prides itself on its publication output. He says that he is happy with the ethical safeguards that are presently in place, but stresses that it is an ongoing, “lifelong” process to instill the appropriate values in SGH’s researchers.

“Medical school is a good start but lectures are just laying some of the foundations,” he says, noting that researchers continue to learn from their peers through an informal mentorship network. The hospital has also been strengthening its educational agenda – offering additional courses and seminars which, Fong says, have been received with enthusiasm by researchers. A recently launched 2-day workshop, focusing on the ethics of GCP and involving speakers from both academia and industry, was heavily oversubscribed, he notes. SGH also implemented a “whistleblower” policy in 2007 to help protect the integrity of its research – allowing researchers to report fraudulent activities without fear of reprisals, and enabling an independent investigation to be undertaken.

Fong adds that it is important to maintain a balance where the frontiers of knowledge and technology can continue to be pushed but without sacrificing patient safety in the process. “As in all things in science, to compete is good, but we don’t want people to compete at all costs. At SGH I think there is a balance – we want to emphasize that it’s not so serious that if you don’t publish you will perish,” he says.

Although Southeast Asia has so far been spared the type of incident where patients are put at risk, the research community here must continue to strengthen its defenses, according to Dr. Thiru Thirumoorthy, a former director of the Singapore Medical Association’s Centre for Medical Ethics and Professionalism. He believes that the rofecoxib story should serve as a wake-up call for the rest of the world, and draws attention to the wider ethical issues of conflicts of interest and the relationships between doctors and pharmaceutical companies.

“Of course the pharmaceutical industries are much bigger in the US so they have greater stakes, but this is by no means purely an American condition,” he says. “The lesson to learn is for us not to reach this point. We should have already put up our barriers much earlier.”

Thirumoorthy believes that in Singapore, in general, the relationships between academia and industry are relatively well moderated at present, but notes that in the absence of definitive evidence the community should remain on guard against complacency. “The first question we need to ask is do we have a problem and is it severe enough for us to do something more? At the moment there is no obvious evidence that it has reached a stage of an exploitative nature. There may be incidences that we do not know of but until such time we should continue to work on education and enforcing guidelines to improve the situation.”

Ultimately, however, only time will tell whether the global medical community is doing enough to protect itself, and whether the public’s faith in medical research can ever be fully restored. Despite the profession’s best attempts to tighten its defenses, it may simply be a matter of time until its values are once again left cruelly exposed.

“We’re doing our best to try to keep people honest but I’d be a fool to say that it won’t happen again,” concludes Drazen. We’re protecting against things that happened in the past but somebody will be creative and come up with something new and there’s nothing you can do about it. If someone wants to cheat badly enough, they’ll succeed.”

Professor Jeffrey Drazen was in Singapore as part of the National University Health System’s Distinguished Editors Series.

Darwin’s legacy in the balance: The splendor of the Galapagos Islands

Medical Tribune March 2009 P18
David Brill

The Galapagos Islands are treasured by naturalists the world over for their unrivalled diversity of wildlife and geology. David Brill visits the islands, and reports on the difficult challenges they face.

February 12th saw the world celebrate the life of one of its great scientific heroes. Two hundred years on from the birth of Charles Darwin, and 150 from the publication of his much-celebrated On the Origin of the Species, his theories of natural selection continue to this day to shape our understanding of the world around us and our appreciation of the history of mankind.

The Galapagos Islands, located around 1,000 km to the west of mainland Ecuador, played an integral role in the development of Darwin’s theories. He visited the archipelago in 1835 aboard the HMS Beagle, on its way back to England from a 3-year voyage around the coastlines of South America. An enthusiastic naturalist with a seemingly limitless capacity for taking notes and collecting specimens, it was here that he acquired the data which were to famously mould his thinking on evolution. The different sub-species of finch, each one perfectly adapted to its niche on the respective islands, has become perhaps the best-cited example of his inspiration.

To visit the Galapagos Islands today is to grapple with a difficult ethical dilemma. The national park authorities depend on the income from tourism to enact the conservation projects that seek to preserve the islands’ unique ecosystems, yet it is the influx of tourists which hastens their very demise. The annual number of visitors rose from 68,856 in 2000 to 108,436 in 2004 – pairing a substantial rise in income with an equivalent threat from pollution and the introduction of non-native species. Andrew Marr, president of the Galapagos Conservation Trust (GCT), warned recently that development needs to be brought under control, and suggested that tourists be restricted to one visit per lifetime. Marr himself, a well known British journalist and commentator, has pledged never to return despite falling in love with the islands on a visit in 2002 and taking up the GCT presidency in 2006.

For those who do exercise their right to make this literal once-in-a-lifetime trip, it is easy to see why Marr feels so strongly about the preservation of the Galapagos Islands. The beauty and diversity are every bit as spectacular as promised, and can scarcely be captured in words or photographs. There can be few spots in the world where you can watch a mother hawk teaching her young to swoop for marine iguanas, which scurry for cover in the cracks of a scarred volcanic landscape. With sea lions sunbathing on bright white sand to your left, albatrosses circling a haunted-looking scrub of a forest to your right, and giant turtles peeking their heads out from the shining blue ocean ahead of you, the list of possible locations is surely shortened to one.

The Galapagos Islands sit on a tectonic conveyor belt above a submarine volcanic hotspot. As new cone-shaped islands rise up from the seabed, they begin to move slowly away from the lava source, becoming cool and inactive as they are carried east and eventually worn down by erosion. At a pace of 75 mm per year this is a slow process: Espaňola, the oldest of the 13 main islands, is estimated to be around 4 million years old while Fernandina is the youngest at under a million years and remains volcanically active to this day.

It is this diversity of geology that has given rise to the islands’ astonishing range of wildlife, fostering the evolution of several species which do not exist anywhere else in the world. While Fernandina sits barren and lifeless, its red rocks resembling a Martian landscape, Espaňola is green and verdant and contains many of the natives endemic to the Galapagos. In the middle sits Santa Cruz, the second largest of the islands and home to Puerto Ayora, the major population center of the islands. Santa Cruz is also the residence of Lonesome George – the world’s last surviving giant Pinta tortoise and the most famous citizen of the Galapagos (pictured). Despite countless attempts to encourage him to bear offspring he continues to live out his days as a bachelor at the Charles Darwin Research Station, apparently oblivious to the demise of his species and the iconic status he has gained among environmentalists.

There are signs that tourism in the Galapagos Islands is slowing in the current economic climate. Some of the cruise liners have received unusually high numbers of cancellations and are down-scaling their itineraries for this year. It remains to be seen how the islands will cope with this drop in the income which has become such a double-edged lifeline, and whether the unique beauty of the Galapagos will benefit or suffer from this downturn. As long as tourism can be appropriately managed and regulated, however, there is little doubt that the Galapagos Islands will remain one of the world’s greatest destinations – as inspiring to travelers today as they were to Darwin himself.