Caffeine in pregnancy restricts fetal growth, study warns

Medical Tribune February 2009 P6

David Brill

Consuming caffeine during pregnancy can significantly increase the risk of fetal growth restriction, according to one of the largest and most comprehensive studies to weigh in on a notoriously inconclusive debate.

Pregnant women are typically advised to reduce their caffeine intake as a sensible precaution, but research findings have been inconsistent and a definitive link to birth defects has remained elusive.

The new study, which claims to be the first to give a “true picture” of caffeine intake in pregnancy, found that the association was significant at all levels of consumption and continued throughout pregnancy.

The size of the effect is similar to that seen for alcohol consumption, the UK researchers reported in the British Medical Journal. [2008 337:a2332] They recruited 2,635 low-risk women at 8 to 12 weeks of pregnancy and followed them up until birth.

An intake of more than 200 mg/day of caffeine was linked to an average birth weight reduction of up to 70g (P = 0.004) and increased the odds ratio for having a growth restricted baby to 1.5, as compared to an intake of below 100 mg/day (P = 0.02).

Dr. Shephali Tagore, an associate consultant in the department of maternal fetal medicine at KK Women’s and Children’s Hospital, Singapore, said the study confirms that the advice to reduce caffeine intake before and during pregnancy is appropriate.

“While previous studies have suggested a risk, this study group has objectively quantified caffeine from all known sources. This is a major strength of the study. They have found a dose-response relationship, showing that increasing caffeine intake was associated with increasing risk of fetal growth restriction,” she said.

Tagore added, however, that it is difficult to draw firm conclusions from the paper since there was no control group of women who did not consume any caffeine during pregnancy,

Previous studies have overestimated the impact of tea and coffee and relied too heavily on retrospective recall of caffeine consumption, according to the authors, who took a more thorough approach by using a comprehensive questionnaire which was validated against food diaries and saliva samples.

They found that only 14 percent of the women’s caffeine intake came from coffee. Tea was the major source, comprising 62 percent of intake, with cola drinks and chocolate contributing 12 and 8 percent respectively.

“We believe that, for the first time, this reflects a true picture of total caffeine intake by women during pregnancy,” they wrote. “Our findings emphasize the weakness of studies where caffeine intake was equated to that of coffee alone.”

Caffeine is absorbed rapidly and can cross the placenta freely. The main enzyme for breaking down the compound, however, is not found in the placenta or fetus so exposure depends largely on maternal metabolism.

To investigate whether individual metabolic differences affected fetal growth the researchers also measured the half-life of caffeine in the women’s saliva. The association with fetal growth restriction was strongest in women who had the fastest caffeine clearance but this result did not reach significance (P=0.06).

Caffeine consumption has also been linked to miscarriage. A study published last year found that an intake above 200mg/day more than doubled the risk. [Am J Obstet Gynecol 2008 Mar;198(3):279.e1-8]

Another recent study found that injecting the caffeine equivalent of two cups of coffee into pregnant mice decreased cardiac function and stunted development of the cardiac ventricles in their offspring. [FASEB J 2008 Dec 16 Epub ahead of print]

Southeast Asia aligns with JUPITER

Medical Tribune February 2009 P9
(Indonesia / Philippines edition only)
David Brill

Experts in Southeast Asia are responding with cautious optimism to the landmark JUPITER* study, which dominated headlines at the recent American Heart Association conference in the US.

While there are several important messages to draw from the study doctors should not rush to incorporate the findings into routine practice, specialists from the region told Medical Tribune.

Local guidelines are not anticipated to change in the immediate future, they said.

JUPITER – a randomized controlled trial of 17,802 participants – demonstrated that rosuvastatin, as compared to placebo, significantly reduced major cardiovascular event rates in overtly healthy people with normal LDL-cholesterol but elevated high-sensitivity C-reactive protein (hsCRP) levels. [N Engl J Med 2008 Nov 20;359(21):2195-207] The study has moved hsCRP into the limelight and prompted some international experts to call for the biomarker to take a more prominent role in cardiovascular risk stratification.

Professor Cheuk-Man Yu, head of the division of cardiology at the Chinese University of Hong Kong, said that the reduction of cardiovascular events in the study was “highly encouraging” for both physicians and patients but noted that more research is still needed into the pathophysiological mechanisms that underlie the effect.

“It will be difficult to generalize this into routine practice without further understanding the relationship between lipid lowering, reduction of vascular inflammation and reducing atherosclerosis,” he said.

“I don’t think we fully understand the hsCRP story. From this study it does seem to be a very important mediator for underlying vascular disease but we still haven’t got the definite answer as to whether it is a stand-alone risk factor or just a manifestation of the accumulated conventional risk factors.”

hsCRP levels can be altered by a number of factors and may not be solely a marker of inflammation in vascular plaques, said Yu, noting that bacterial and viral infections, rheumatoid arthritis, tuberculosis and lupus erythematosus can all increase levels of the biomarker. These potential explanations would all need to be ruled out, and all conventional risk factors worked upon, before considering intervention on the basis of an elevated hsCRP alone, he said.

Associate Professor Terrance Chua, chairman of the Singapore Heart Foundation, said that he expects hsCRP testing to “take on a bigger role” in risk assessment, in light of the data from JUPITER.

“It would be useful in a situation where a patient is at intermediate risk and one is trying to make a decision whether or not to initiate lipid-lowering therapy. hsCRP may help to further refine the risk and cast the deciding vote on whether or not to start treatment in these patients. We will have to wait and see how the guidelines committee absorbs this information,” he said.

Chua also noted that the JUPITER results are consistent with those of previous statin trials and provide further reassurance as to the benefits of cholesterol-lowering therapy. He added, however, that it is important not to lose sight of the importance of non-pharmaceutical interventions such as diet.

“The great challenge is really to try to change lifestyle,” he said. “It’s a bigger challenge than taking a tablet but if we want to have a truly cost-effective way of dealing with the growing problem then changing lifestyle would obviously be more effective.”

Dato’ Seri Dr. Robaayah Zambahari, senior consultant cardiologist at the National Heart Institute in Kuala Lumpur, Malaysia, said that she believes strongly in the benefits of statins for secondary prevention but that the risk-to-benefit ratio will need to be reviewed before adopting a primary prevention strategy.

She added that JUPITER did not address the long-term safety of rosuvastatin since the trial was stopped after just 1.9 years.

-------------------------------------------------
*Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin

Low glycemic index diet boosts glucose control and HDL in diabetics

Medical Tribune February 2009 P10
David Brill

Following a low glycemic index (GI) diet can improve blood sugar control and raise HDL-cholesterol levels in type 2 diabetics, according to a recent study in the Journal of the American Medical Association.

Researchers from St. Michael’s Hospital and the University of Toronto, Canada, randomized 210 patients to follow either a low-GI diet or a high-cereal fiber diet for 6 months.

At the end of the study, HbA1C had decreased by 0.5 percentage points among those in the low-GI diet group, compared to just 0.18 percentage points in those following the high-cereal fiber diet. When comparing the two diets the relative change in HbA1C was 0.33 percent (P<0.001). p="0.005).">JAMA 2008 Dec 17;300(23):2742-53]

Participants in the trial all had HbA1C values between 6.5 and 8 percent at baseline screening, and had not had their diabetes medications changed within the preceding 3 months.

The European Society of Cardiology (ESC) said in a statement that the study supports current recommendations on lifestyle advice for the control of diabetes.

“Treatment of type 2 diabetes should always be initiated with structured lifestyle advice. Results from the JAMA study suggest that such advice may be as effective as some drug interventions,” said ESC spokesman for diabetes and cardiovascular disease Professor Lars Ryden of the Karolinska University Hospital, Sweden.

“The JAMA study also shows that a well-balanced diet will improve not only blood glucose tolerance but also blood lipid levels, which are of great importance in decreasing cardiovascular complications. If drugs are still needed in these circumstances, their dose and number may be lower,” he added.

The usefulness of GI as a dietary guide has proved controversial in the past. The index gives a measure of the extent to which certain foods affect the body’s glucose levels, but critics have questioned the methodology used to determine the values. [Diabetes Care 2003 Aug;26(8):2466-8]

The American Diabetes Association does not specifically advocate the low-GI diet, but notes on its website that it “may be helpful in ‘fine-tuning’ blood glucose management” and could provide additional benefits for those individuals who wish to pay close attention to their dietary choices.

Another recent trial, involving 162 type 2 diabetics, found that following a low-GI diet for a year did not improve glycemic control compared to a high-GI diet, although it did reduce postprandial glucose and C-reactive protein levels. [Am J Clin Nutr 2008 Jan;87(1):114-25]

Alexander technique beneficial and cost-effective for chronic back pain sufferers

Medical Tribune February 2009 SFIV

David Brill

Teaching the Alexander technique could be an effective and cost-efficient way to treat long-term chronic back pain, the results of a recent randomized controlled trial suggest.

Patients who received a series of 24 lessons scored significantly lower on a disability scale 1 year later and spent considerably fewer days in pain than those in the control group.

Six lessons in combination with an exercise prescription was slightly less beneficial but was the most cost-effective option for treating back pain in the primary care setting, the researchers reported.

The Alexander Technique is a method for improving posture, balance and co-ordination, with a particular focus on releasing tension in the spine, neck and head.

The trial included 579 chronic or recurrent back pain sufferers and took place at 64 general practices in the UK. It is the first study to look at long-term outcomes of the technique in back pain, according to the authors, who published the trial findings and economic evaluation in two separate British Medical Journal papers. [2008 337:a884; 2008 337:a2656]

Patients were randomized to normal care, 6 sessions of therapeutic massage, or 6 or 24 lessons of the Alexander technique. Half of each group also received an exercise prescription from their doctor and behavioral counseling from a practice nurse.

Those receiving 24 Alexander technique lessons alone scored, on average, 3.4 points lower on the Roland Morris disability score at 1-year follow-up compared to those in the control group. This group also reported experiencing back pain on just 3 days out of the preceding 4 weeks, whereas control subjects reported pain on a median of 21 days during this period. Adherence was high and there were no adverse events reported for either exercise or the Alexander technique.

Six lessons combined with exercise yielded 72 percent of the beneficial effects of 24 lessons alone but was the most economically viable combination, costing an additional £64 (US$ 94) per point on the disability scale, £43 (US$63) per pain-free day, and £5,332 (US$7,855) per quality-adjusted life year gain.

The massage intervention was beneficial at 3-month follow-up but had no significant effects after 1 year.

Back pain is a common cause of primary care consultations, with an annual prevalence thought to range from 15 to 45 percent. It is the second most common reason for a visit to the physician in the US and the number one cause of activity limitation in under-45s. [Lancet 1999 Aug 14;354(9178):581-5]

Integrity and objectivity on trial: The enduring legacy of rofecoxib

Medical Tribune February 2009 SFVI
David Brill

The events surrounding the withdrawal of rofecoxib shattered the widely held assumption that medical research serves to protect the public interest. In the first of a two-part series, Medical Tribune’s David Brill speaks exclusively to two of the central characters in the story of the key rofecoxib trial to find out what happened and what they have learned from the affair.

On December 29th 2005, the public’s fragile faith in medical research took another near-fatal blow. The withdrawal of the multi-billion dollar ‘blockbuster’ arthritis drug rofecoxib (Vioxx) the year before had been testing enough, but the latest revelation that safety data had been concealed in a key clinical trial of the drug was the final straw. The notions of objectivity and integrity that had lain at the very heart of research were exposed to an intense and damning scrutiny that continues to dominate both the academic and lay press to this day.

Rofecoxib, a selective cyclooxygenase-2 inhibitor, was voluntarily withdrawn in September 2004 by its manufacturers Merck & Co., which announced that ongoing research had shown definitively that the drug raised the risk of cardiovascular events. The news was shocking enough for the academic community – concerns had been repeatedly expressed but had largely gone unheeded by the manufacturers – but for the public the sheer magnitude of the decision was devastating. The drug had been on sale for more than 5 years in over 80 countries – leaving millions of people exposed to potentially avoidable heart attacks and strokes.

The affair left a profound legacy for the entire medical profession but for the members of the International Committee of Medical Journal Editors (ICMJE), it was a particularly bitter pill to swallow. Three years before the announcement they had warned in an editorial that the “precious objectivity” of medical research was under threat from the growing involvement of corporate sponsors in clinical trials which, they said, was allowing companies to increasingly dictate their own terms regarding the design, interpretation and publication of clinical trials. The gravity of the warning was clear but the timing of publication – September 10th 2001 – proved to be unfortunate when events in New York the following day pushed the discussion of medical ethics firmly to the bottom of the news agenda.

Objectivity and integrity are core values for all of the medical journals but for none is the weight of expectation greater than for the New England Journal of Medicine (NEJM). The journal – perceived by many researchers as the ultimate outlet in which to publish their work – has the highest impact factor of any medical journal and bestows upon its papers an inherent authority and prestige that only one or two other publications could claim to match. In 2007 alone the NEJM received some 6,000 original research papers, of which just 5 percent were published.

It was to the consternation of its editors, therefore, that the NEJM was to find itself sucked into the post-rofecoxib storm. As the legal process continued, attention turned to its November 2000 publication of the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial, comparing the gastrointestinal toxicity of rofecoxib with naproxen in 8,076 rheumatoid arthritis patients. [23;343(21):1520-8] The plot had already begun to thicken in 2001 when an updated data set from the trial was presented to the US FDA, showing that three extra myocardial infarctions (MIs) in the rofecoxib group had occurred shortly after the cut-off point for the reporting of adverse events – results that, had they been included in the VIGOR analysis, would have increased the relative risk of MI from 4.25 to 5.00 for patients taking rofecoxib.

The NEJM editors were reassured that these were “late data” which had only been discovered after publication, but in November 2005 they learned that all was not as it had seemed. The extra MIs had, it emerged, been known about almost 5 months before the publication of VIGOR, giving the authors ample opportunity to include them in the 2000 paper. The NEJM announced the news by publishing an “Expression of Concern” on December 29th 2005, highlighting the “misleading conclusion” of the trial and questioning the integrity of its data. [29;353(26):2813-4]

For Professor Jeffrey Drazen, the journal’s editor-in-chief, the lesson of the story is clear. “We used to assume that everybody understood the rules. Now we no longer expect that people will play by them,” he explained on a recent visit to Singapore.

“When we discovered the extra events the authors said ‘well, we don’t know about this’. And in fact they didn’t.” It was hidden from them, says Drazen. “The violation of ethics, in my opinion, was not putting the material out in the open. So in retrospect, when it became clear that there was a discrepancy between what was in our pages and the data set sent to the FDA, we should have been more aggressive about querying the authors.”

The NEJM now takes a more direct interest in adverse event reporting when it comes to assessing the design of trials, according to Drazen. An unusual situation had arisen in VIGOR whereby the closing date for reporting GI bleeds – the study’s primary endpoint – was extended beyond the closure of the adverse event database. The trial continued for several weeks, but the additional cardiovascular events that occurred during this window were not included.

“They designed the trial in a sneaky way and never told anybody about it. Now we’re smart enough to ask about this. We want adverse event reporting up to the day of acceptance, not as of some prespecified day.”

Demanding accountability for the data is perhaps the most important lesson that the NEJM has learned from rofecoxib but now, Drazen says, they have “turned it around” by attaching a stronger sense of responsibility to research authorship. A study printed in the journal today may appear overtly similar to one published pre-rofecoxib, but a closer look at the methods section now reveals the key statement: “All authors had full access to the data and vouch for the accuracy and completeness of the data and the analyses.”

“The most important thing you have as an academic researcher is your reputation,” explains Drazen. “If you want to maintain your reputation you have to go to the company and say ‘I can’t put my name on this paper until I’m sure that the data I’m reporting are accurate and complete. I need to be sure that it’s my paper.’ Had we had such a statement from the authors we’d have been able to go back and tell them that they had committed perjury but we couldn’t do that.”

For Professor Richard Day, one of the academic authors of the VIGOR study, this is a lesson which had to be learned the hard way. The years that followed the NEJM’s Expression of Concern were difficult and distressing for him. Not only had his high hopes for rofecoxib been destroyed with the withdrawal of the drug, but now his name and those of his co-authors had been dragged down into the realms of scandal.

“It was a challenging time – there were lawyers engaged all over the place to try to put forward the positions of the various parties and it was all pretty unpleasant. I think we got pretty severely beaten up from all sides,” he says.

Day, a professor of clinical pharmacology at the University of New South Wales in Sydney, Australia, confirms Drazen’s assessment that the academic investigators were kept in the dark about the extra adverse events in VIGOR and feels that much of the “angst and uproar” could have been avoided had these data been discussed with them. He stands firmly behind the study itself, however, feeling that the issue of the extra MIs has been allowed to overshadow what was the largest trial of its kind and an exciting opportunity to tackle the huge problem of gastrointestinal bleeds.

“In my view it’s one of the best studies ever done in the field of rheumatoid arthritis. It has not been recognized for its quality because of this one issue. It’s an important issue, but it’s ruined it in lots of ways,” he says.

It was a strange and ultimately poor decision not to include the extra events, according to Day, but he notes that from a purist’s perspective it was technically correct since the prespecified trial protocol had demanded that they be excluded. The contentious extension of the GI events window was at the request of the academic authors, he adds, noting that it was an endpoint-driven study and that the researchers had simply wanted to accrue as much data as possible about the benefits of rofecoxib. Why the adverse events window was not also extended accordingly he does not know.

The complete story of rofecoxib and VIGOR may never be revealed but for now the scar on the public consciousness endures. Perhaps surprisingly, however, Day feels that despite the “collateral damage” suffered along the way, the long-term legacy of the affair may ultimately help to rebuild the integrity which it once destroyed.

“Clearly the light’s being shone more and more on this interaction between the clinical world and drug companies and that’s a good thing,” he concludes. “I’m sure there’ll be more problems but I think with every one of them we learn, tighten up and try to head them off so that in future we can believe what we see, read and hear, and feel that it represents a proper treatment of data and opinions which is independent and addresses conflicts properly.”

An edited version of this article appeared in Medical Tribune.

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

Next month: David Brill looks at how the integrity of medical research can be restored through the lessons learned from rofecoxib.

Simple strategy effective in postpartum depression screening

Medical Tribune February 2009 P16
David Brill

Combining two existing screening tools could be a straightforward, time-saving and effective way to detect postpartum depression (PPD) in primary care, US research has shown.

The first screening stage, comprising two simple yes/no questions, was 100 percent sensitive at detecting PPD, according to the Annals of Family Medicine study. [2009; 7:63-70]

Patients with a positive result on the two-question screen should then progress onto the nine-item Patient Questionnaire (PHQ-9), say the University of Minnesota researchers, who report that this second stage was 92 percent specific. They tested the two-tiered strategy in 506 women who brought their newborn infants for well-child visits at pediatric and family medicine clinics over the course of 9 months.

The screening tools have already been incorporated into routine practice at several Minnesota clinics and are soon to be implemented in three large hospitals, according to Dr. Dwenda Gjerdingen, who led the study.

“We find them easy to administer, patients find them easy to complete, and they give us a good sense of where the patient is at in terms of their mental health,” she said.

“You want your initial screen to be highly sensitive, which this one is: the two-question screen does not miss depressed patients. Then the PHQ-9 is a very specific test so when depressed people complete it and it turns out to be positive, it is likely to be a true positive and not a false positive.”

The two-question screen focuses on the main symptoms of depression: diminished mood and loss of pleasure in activities.

Despite the common nature of PPD – the condition affects around 22 percent of new mothers and is the most common complication of childbirth – less than half of mothers are presently being screened, the authors wrote. The condition not only affects the mother’s wellbeing but can also harm the cognitive development of the infant. [Arch Womens Ment Health 2003 Nov;6(4):263-74]

The results of the new strategy were validated against the Structured Clinical Interview from the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV. Forty-five (8.9 percent) of the women were found to have major depression.

Gjerdingen noted that the PHQ-9 still missed a few depressed patients, so suspicion should be retained in those who achieve a negative result having scored positively on the initial two-question screen. These women should be advised to see their doctor if they experience a dip in mood, she said.

Both the two-question screen and the PHQ-9 are already used in general depression but had yet to be validated in PPD. Other potential screening options for PPD are available but typically take longer to complete, Gjerdingen said.

Journal editorials fuel unfounded brand-name bias

Medical Tribune Unpublished
David Brill

Medical opinion leaders are adding to unnecessary spending by promoting the misperception that generic cardiovascular drugs are inferior to brand-name versions, a recent study suggests.

In a thorough systematic review and meta-analysis comprising 47 studies, researchers from Harvard Medical School, US, found that generic cardiovascular drugs were equivalent to brand-name drugs in almost all clinical outcomes.

They also observed, however, that more than half of the relevant journal editorials and commentaries published over the same period expressed negative views about the substitution of these medications.

“Unfortunately, in general, generic drugs are relatively under-used because there are a lot of misperceptions out there that they might somehow be inferior to brand-name drugs,” said Dr. Aaron Kesselheim, lead author of the Journal of the American Medical Association paper. [2008 Dec 3;300(21):2514-26]

“The best way to combat these misperceptions is by looking at the data so that’s what we tried to do. There was no evidence that brand-name drugs are superior to generic drugs,” he said, adding that the study is the first to his knowledge to take such a comprehensive approach to summarizing the literature in this field.

The rising cost of brand-name drugs is not only creating a financial burden but also directly contributing to poor health outcomes, the researchers wrote, citing a study which found that the promotion of generic or preferred medications improved adherence. [Arch Intern Med 2006 Feb 13;166(3):332-7]

Kesselheim called on both the authors and publishers of editorials to take greater responsibility for ensuring that opinion pieces have a reasonable evidence base and present both sides of the argument when the data are conflicting.

“Doctors look to these journals as a source of medical information and that can influence a lot of prescribing practices. It seems that that the general message of a lot of these editorials was not in concert with what the data show,” he said.

The research did not address the reasons underlying these negative attitudes but Kesselheim speculated that physicians may have “fallen into the same cognitive trap” as patients, who tend to naturally associate the word generic with meaning lower quality.

“Another alternative is that some of the physicians who are writing these editorials might have financial relationships with brand-name drug companies that color their opinion of brand-name drugs as compared to generic drugs,” he added.

The meta-analysis included 38 randomized controlled trials (RCTs) and nine retrospective studies addressing the clinical equivalence of nine different cardiovascular drug subclasses. Only FDA-approved brand-name medications were assessed.

Clinical equivalence was observed in all seven RCTs of beta-blockers, five out of seven RCTs of calcium channel blockers and 10 out of 11 RCTs of diuretics. All of the remaining RCTs – covering statins, antiplatelets, alpha-blockers, angiotensin-converting enzyme inhibitors, class 1 antiarrhythmics and warfarin – demonstrated the clinical equivalence of generic medications.

“The implications are that physicians can feel confident prescribing generic drugs for their patients with cardiovascular disease when appropriate for their condition … and patients can be confident that they’ll be getting the same clinical effects that they might be getting with a brand-name drug,” said Kesselheim, who is an instructor in medicine at Harvard Medical School.

The literature review and content analysis included 43 editorials, 23 of which were deemed to have a negative stance towards generic drug substitution. Twelve articles were in favor of the practice and eight were neutral.

Experts fear rise of drug-resistant superbug

Medical Tribune January 2009 P1&6
David Brill

Rising levels of drug resistance among Acinetobacter Baumannii are causing serious concern among infectious disease experts, who are calling for urgent international attention to the issue.

The bug is particularly prevalent in hospitals in Southeast Asia, with Taiwan and Korea seemingly the worst affected.

The rapidly dwindling number of treatment options could soon herald the dawn of the “post-antibiotic era,” according to a specialist from Singapore, where extensively drug-resistant strains have already been reported.

A. Baumannii resistance rates are increasing globally, with around half of strains presently thought to be resistant to at least one antibiotic. Nearly 20 percent of strains are resistant to all but one or two agents.

Reports have already emerged of pandrug resistant strains, which – although rare at present – will beome increasingly common if the problem is not addressed, said Professor Matthew Falagas, an international expert who published a recent high-profile review calling for more research into treatment options. [Lancet Infect Dis 2008 Dec;8(12):751-62]

“We should be worried because we have never heard before of bugs which affect humans where we do not have an antibiotic to provide,” he told Medical Tribune.

“The issue of pan-drug resistance needs international attention. Public health organizations and local infection controls at the country level should disseminate guidelines on this issue,” he said, adding that in some hospitals the significance of the bug is already on a par with methicillin-resistant S. Aureus (MRSA).

A. Baumannii mainly affects seriously ill patients in intensive care units and burn wards. Although less common than other hospital-based infections, the bug can cause significant morbidity and mortality, placing a heavy drain upon hospital resources through repeated hospitalizations and increased lengths of stay.

A Singapore study found that 69 percent of A. Baumannii strains in one intensive care unit were resistant to carbapenem. Nearly 20 percent of isolates from all the nation’s hospitals were resistant to everything except the polymixins, which can cause significant toxicity to the brain and kidneys. [Emerg Infect Dis 2007 Dec;13(12):1944-7]

“Its ability to acquire resistance is a big concern because there aren’t going to be many treatment options available,” said Dr. Tan Thuan Tong, an infectious diseases consultant at Singapore General Hospital.

“We foresee a time when you get strains that are not treatable and you just try your luck with various combinations that might act in a synergistic manner,” he said, adding that such a scenario could arise in Singapore within the next 5 years.

Around 30 to 40 percent of patients who get a multidrug-resistant A. Baumannii bloodstream infection may die, according to Tan, but he added that the directly attributable mortality is not clear-cut since patients are often critically ill for other reasons.

Falagas, meanwhile, called on hospitals worldwide to decrease the usage of antibiotics and promote stricter infection prevention and control measures, particularly with regard to hand hygiene. He added that research is now ongoing to find new antibiotics for Gram-negative bacteria, but said that the process has been too slow getting started.

“The scientific community and the pharmaceutical companies have focused attention on Gram-positives without understanding the significance of Gram-negatives as healthcare-associated infections, and especially A. Baumannii,” said Falagas, who is director of the Alfa Institute of Biomedical Sciences in Athens, Greece, and an adjunct associate professor at Tufts University
School of Medicine, Boston, US.

Singapore has already begun to acknowledge the growing problem of antimicrobial resistance, with a group of experts publishing a recent position paper advocating stricter controls on the use of antibiotics. [Singapore Med J 2008 Oct;49(10):749-55]

“In the 18th and 19th century, there were no antibiotics and treatment was with drainage of pus, amputation and other surgical approaches. If you have infections with these untreatable bugs, then you are back to the days when you can’t do anything,” added Tan.

hsCRP: A new player on the cardiovascular risk stratification stage

Medical Tribune January 2009 P2&3

Dr. Jacques Genest, director of cardiology and Novartis Chair in Medicine at McGill University, Montreal, Canada, addresses the emerging role of high-sensitivity C-reactive protein in predicting cardiovascular risk.

High-sensitivity C-reactive protein (hsCRP) represents a new paradigm in the assessment of cardiovascular risk. It is set to become the first new biomarker for 30 years to be incorporated into routine clinical practice alongside traditional tests such as blood pressure and cholesterol. Guidelines across the world are under review, and it is only a matter of time before hsCRP becomes an integral tool in the risk stratification armory of the primary care physician.

The recent Justification for the Use of Statins in Prevention (JUPITER) trial showed that treating patients who had elevated hsCRP in the absence of other risk factors could significantly reduce the incidence of major cardiovascular events. After a median of 1.9 years of follow-up, the occurrence of cardiovascular death, myocardial infarction, stroke, arterial revascularization or hospitalization for angina was reduced by 44 percent in those treated with rosuvastatin (20mg daily). [N Engl J Med 2008 Nov 20;359(21):2195-207]

These results do not justify testing everyone for hsCRP, but rather suggest that the test will be of great benefit for patients who occupy the grey area between low and high risk. A high hsCRP score can push a debatable case over the treatment threshold while a low score, conversely, can confirm that the patient does not require treatment. Those already deemed to be at high-risk should receive treatment regardless of hsCRP, so the test will add little prognostic value in these patients, while at the other end of the scale there is not sufficient evidence to support routine hsCRP testing in young, healthy people with no other risk factors.

Physicians should begin, therefore, by performing a full and complete cardiovascular risk stratification including sex (until menopause in women), age, physical activity levels, diet, diabetic status, blood pressure and LDL, HDL and total cholesterol levels. For patients who are not obviously at high or very low risk, the physician should now routinely include an hsCRP test. Present evidence suggests that this strategy should be adopted in all men aged over 50 and women aged over 60 – the population that was successfully targeted for treatment in JUPITER. In my opinion, hsCRP will ultimately prove to be of use in men aged over 40 and all postmenopausal women, since these years often herald an increasingly sedentary lifestyle whereby the long-term outcome is likely to be heart disease or cancer. We await the support of local guidelines on this point, however, and at present physicians should exercise their own judgment as to the appropriate age for introducing hsCRP testing.

JUPITER treated patients with hsCRP levels of 2.0 mg/l or higher, and physicians may wish to adopt this level as their cut-point for deciding whether to initiate treatment. There is, however, strong epidemiological data and an ongoing argument in support of adopting a threshold of 3.0 mg/l or higher. This, again, will prove a matter for the guideline makers to decide and is likely to vary from country to country. For those with socialized medicine the cost implications of adopting the lower threshold will be considerable, and will prove an important factor in this decision.

Introducing routine hsCRP testing will undoubtedly increase the number of patients being treated with statins. We must not lose sight, however, of the continued importance of diet and lifestyle interventions, for which there is incontrovertible evidence in favor. Physicians should continue to press the message on five fronts: smoking cessation, quality of diet, quantity of diet, daily exercise, and serenity. The latter encompasses both stress management and levels of social interaction – both important prognostic factors in long-term mortality outcomes. Addressing these issues in a single consultation can be difficult – particularly when seeing the patient only once every 6 to 9 months – and I would recommend that GPs refer certain cases to a dietician and kinesiologist in order to improve motivation through more regular advice and feedback.

Many biomarkers have come and gone over the past 20 years of my research career but very few have proven to be clinically useful. Homocysteine, inflammatory factors, cell adhesion molecules, matrix metalloproteinases, and enzymes such as lipoprotein-associated phospholipase A2 have all failed or are still not ready for primetime use. These markers may predict disease but that does not mean that targeting them will automatically yield a reduction in hard clinical trial endpoints.

The journey towards hsCRP testing has been a long one but the marker has finally matched our ability to predict with our ability to prevent, while also asserting its independence from other risk factors. Guidelines will change in time, but in the face of the evidence from JUPITER physicians may decide not to wait. The time is right, in my opinion, to begin measuring hsCRP and implementing the appropriate strategies in the JUPITER-like patient while we await further international guidance. Unlike other biomarkers, hsCRP testing is here for good.

Dr. Genest is one of the investigators of the JUPITER trial and reports receiving consulting fees from AstraZeneca, Merck, Merck Frosst, Schering-Plough, Pfizer, Novartis, Resverlogix and Sanofi-Aventis.

Placebo prescriptions leave patients in the dark

Medical Tribune January 2009 P4
David Brill

US physicians regularly prescribe placebo treatments but are rarely open with their patients about doing so, a recent study suggests.

Sixty-two percent of physicians who completed a postal survey said that prescribing placebos was ethically permissible, and almost half reported doing so at least 2 or 3 times per month.

However just 5 percent of those who gave placebos said that they explicitly described them as such to their patients. The majority – around two thirds – usually described the treatment as a medicine which is not typically used for that particular condition but which might be of benefit.

“Our study seems to suggest that doctors may be using placebo treatments and they may be cutting corners in terms of how they describe them to patients,” said lead researcher Dr. Jon Tilburt, currently an assistant professor of medicine at the Mayo Clinic, US.

“I don’t think that these data show that doctors are actively deceiving their patients all the time,” he added, noting that the use of truly ‘inactive’ placebos was reported by less than 3 percent of the respondents.

“Physicians rarely use treatments such as sugar pills or saline in which there is no evidence that it could even possibly have a physiological benefit. Those treatments, I think, would be more closely aligned with overt deception,” he said.

Over-the-counter painkillers and vitamins were the most common choices of placebo in the study, with 41 and 38 percent of physicians, respectively, having recommended these treatments in the past year. Sedatives and antibiotics had each been recommended by 13 percent of physicians during that time.

Although the study did not address the complex issues that underlie physicians’ motivations for prescribing placebos, Tilburt believes that in general they have their patients’ best interests at heart when doing so.

“Physicians have a deep impulse to help but when you put them in a circumstance where they cannot fully realize that impulse they still want to do something, even if it comes at some expense to informed consent. And because we don’t have a healthcare system that reimburses for reassurance, good conversations and a quality relationship, we sometimes substitute pills for those more existential aspects of our caring,” he said.

Dr. Thiru Thirumoorthy, a former director of the Singapore Medical Association’s Centre for Medical Ethics and Professionalism, said that placebos have historically been an acceptable part of the healing process in all cultures – particularly among eastern traditions. He noted, however, that doctors need to exercise their judgment before prescribing placebos and must be able to show that they have acted in the patient’s best interests when called to account.

“Placebos must not cause harm, should not take the place of other effective medications, and should not be used unless all other proven treatments have been exhausted or are contraindicated,” he said.

“Placebos should not be used to create a dependency situation. Patient empowerment must be promoted in diseases that do not have effective treatments.”

The survey by Tilburt et al. was completed by 679 practicing rheumatologists and general internists. The researchers defined a placebo as “a treatment whose benefits (in the opinion of the clinician) derive from positive patient expectations and not from the physiological mechanism of the treatment itself.” [BMJ 2008 Oct 23;337:a1938. doi: 10.1136/bmj.a1938]

Future research is directed at understanding whether the power of the placebo effect can be harnessed without keeping patients in the dark, Tilburt said.

“There is some suggestion that even when we tell patients that they’re going to get a placebo there is still some placebo benefit. There’s probably some detriment in the degree of efficacy when you eliminate deception but it’s not totally eliminated, which is fascinating.”

Voluntary counseling could help doctors avoid burnout

Medical Tribune January 2009 P5
David Brill

Short counseling sessions can reduce burnout among doctors and encourage them to make positive changes to their working lives, a new study suggests.

Doctors who volunteered for an intervention program in Norway reported lower levels of emotional exhaustion, worked fewer hours per week and were less likely to be on full-time sick leave a year later.

They were also more likely to seek further professional help, with 53 percent having undergone psychotherapy at 1-year follow-up compared to just 20 percent at the time of enrollment.

Many had already reached high levels of distress and had considered attending the program for quite some time before actually doing so, according to Dr. Karin Rø of the University of Oslo, who led the study.

“The program legitimizes the need for doctors to take a step back for a while and think about their situation,” she said.

“A lot have come back to me and said that it was really important at that time in their life to have somebody to talk to, to get a different perspective on their own situation. Giving a little help, in time, is much better than having to give a lot of help when the situation is much worse.”

Volunteers at Villa Sana – the only center of its kind in Norway – chose between a single one-on-one counseling session of around 6 hours, or a week-long course involving daily lectures followed by group discussions. All sessions were confidential and no medical records were kept. A total of 227 doctors were included in the study, 185 of whom completed 1-year follow-up questionnaires. [BMJ 2008 Nov 11;337:a2004]

Dr. Sim Kang, a consultant psychiatrist at the Institute of Mental Health, Singapore, hailed the research as an important reminder of a timely issue.

“The healthcare profession is certainly susceptible to the onset of burnout if one is not careful about it. The demands of the job are changing and the expectations are quite high from the public nowadays,” he said.

“The symptoms of burnout encroach not just upon the sense of physical tiredness but also the sense that one is mentally wearied and emotionally drained. The message is that if prevention isn’t working and things are getting out of hand then they should seek help.”

Another BMJ study published this year reported that depressed pediatric residents made six times as many medication errors per month as non-depressed residents. [2008 Mar 1;336(7642):488-91]

Rø pointed to this finding as evidence that doctors need to take care of their own wellbeing in order to take care of others.

“When you fly on a plane and the oxygen masks come down you’re supposed to put your own one on before you help anyone who needs it. I think that’s a very good picture of doctors,” she said, adding that she hopes the study will prompt the creation of other similar centers in future.

A year on from the intervention the participants had reduced their mean working hours by an average of 1.6 hours per week. Just 6 percent were on full time sick leave, compared to 35 percent at baseline.

High rates of depression and suicide have been well documented among doctors. A recent study of Brazilian medical students found that as many as 38.1 percent had depressive symptoms, with females particularly susceptible. [BMC Medical Education, in press]

Rø noted that the Norwegian counseling intervention helped the doctors to normalize their situation, having previously felt that they were the only ones experiencing such feelings of distress. They often fail to seek help because they are used to focusing solely on the needs of their patients and do not realize when they are in need of help themselves, she said.

The exact prevalence of depression among the medical community in Asia is largely unknown.

However, Sim encouraged doctors to discuss their feelings of stress and anxiety in informal support groups with their peers whenever possible, adding that he would like to see longer-term data on the sustainability and generalizability of the Norwegian model before advocating the adoption of more formal, structured programs.



Seven tips for avoiding burnout

Dr. Sim Kang, a consultant psychiatrist at the Institute of Mental Health, Singapore, offers his advice on how to de-stress before it gets too late.

1 – Acknowledge and accept that we are all equally vulnerable and can feel trapped and overwhelmed like anyone else. Medical professionals are not superheroes.

2 – Be willing to communicate with others, particularly through informal networks of colleagues, family and friends.

3 – Clarify your responsibilities within the job and resolve any ambiguities that may be causing additional stress.

4 – Determine your own strengths and weaknesses and play to them.

5 – Educate yourself about the symptoms of burnout.

6 – Find time off to unwind and relax.

7 – Group together with your peers to discuss the difficult issues and identify any problems you may be experiencing.

New Singapore heart center offers one-stop shop for multidisciplinary care

Medical Tribune January 2009 SFVI
David Brill

The National University Heart Centre, Singapore (NUHCS), is set to provide a one-stop treatment shop for cardiac patients, the center’s director said recently.

The ongoing redevelopment project will bridge the gap between cardiologists and other specialists within the National University Healthcare System, enabling multiple comorbidities to be treated in just one hospital visit, Associate Professor Tan Huay Cheem told a press conference.

The NUHCS is presently undergoing a sizeable expansion which will also strengthen ties between scientists and clinicians through the creation of a new translational research-focused Cardiovascular Research Institute.

An additional 25,000 outpatient procedures will be performed annually at the NUHCS by 2015 – a projected 45 percent increase on the current capacity of 55,000. The center is due to move into dedicated new facilities by the end of next year, with overall floor space rising around 50 percent and the size of the outpatient clinics increasing threefold by 2011.

Once completed, the NUHCS will focus on four key areas of cardiovascular care: acute coronary syndromes, heart failure, congenital heart disease and vascular medicine.

“Cardiac patients nowadays don’t just have cardiac conditions – they will frequently have other illnesses such as diabetes, kidney failure, or even mental conditions such as depression or anxiety,” said Tan.

“The current arrangement most of the time is that patients will have to come back repeatedly for follow up. What we want to do here is create a one-stop sort of experience where patients could see as many specialists as they need in a single visit.”

Pediatrics, obstetrics and gynecology, respiratory medicine and anesthesia are among the other designated departments which are expected to work more closely with the redeveloped cardiology center. A new division of cardiovascular nursing is also being created as part of the initiative.

Among the planned research projects is the development of a Singapore-specific cardiovascular risk prediction model, said Tan, noting that this will enable doctors to better direct their resources and thereby improve patient outcomes. A state-of-the-art chronic disease management program will also be created as part of the heart failure initiative.

“The vision that we have for the new heart centre is to shape medicine for the future. The mission is to advance health by integrating excellent clinical care with research and education, and the values of our new heart centre will be teamwork, respect, integrity, compassion and excellence,” added Tan.

The expansion is expected to increase the number of doctors at NUHCS by 20 percent and the nurse workforce by 10 percent. The centre will remain on the Kent Ridge campus, housed in a new building on the site of the current dental school.

Cardiovascular disease is currently the second most common cause of death in Singapore and the burden continues to increase. The number of cardiac outpatient visits each year currently stands at around 200,000 nationwide but is projected to rise to 320,000 by 2015.

The NUHCS alone discharged 7,200 inpatients in 2008 but expects this number to reach 10,000 within 7 years. The number of heart attacks treated at the centre almost doubled between 2000 and 2006.

A new dedicated cancer institute is also due to be opened soon by the National University Healthcare System, which comprises the National University Hospital and the National University of Singapore’s Yong Loo Lin School of Medicine.

The NUHCS has been operating since August 2007 within the existing cardiology facilities at the National University Hospital. It is Singapore’s second national cardiac facility, alongside the National Heart Centre at the Outram Park campus.

Gefitinib reduces toxicity for advanced lung cancer patients

Medical Tribune January 2009 P11

David Brill

Gefitinib is a viable second-line alternative to chemotherapy for advanced non-small-cell lung cancer, offering similar survival rates with fewer side effects, a large-scale international study has shown.

The drug represents “an important shift in the treatment paradigm for this disease,” the authors of the INTEREST* trial reported in The Lancet. [2008 Nov 22;372(9652):1809-18]

Patients who took oral gefitinib also had improved quality of life compared to those who received intravenous infusions of docetaxel.

Asian patients, women, non-smokers and patients with adenocarcinoma all had longer survival with gefitinib – echoing the findings of previous trials which have shown the drug to be of particular benefit in these subgroups. Unexpectedly, however, INTEREST also found similar survival patterns with docetaxel, suggesting that these may be generally-applicable prognostic factors unrelated to the specific treatment.

Gefitinib is not currently approved for routine use by the US FDA. However in some Asian countires it is authorized for second-line use. For example in Singapore patients are typically given a choice between second-line treatment options in the event that initial chemotherapy is unsuccessful.

“Should the patient go on to further chemotherapy or should they go on to other drugs like gefitinib? This study confirmed that gefitinib is just as good as chemotherapy but may have fewer side effects,” said Dr. Toh Chee Keong, a consultant medical oncologist at the National Cancer Centre Singapore (NCCS).

Given the choice, most patients prefer an oral drug to chemotherapy but the higher cost of gefitinib can sometimes be a prohibitive factor, he said.

It remains unclear exactly who will benefit most from each treatment and why, he added, but noted that in his experience a non-smoking status is the most powerful predictor of a positive response to gefitinib.

In contrast to previous trials, neither epidermal growth factor receptor (EGFR) gene copy-number nor EGFR protein expression predicted survival with gefitinib in INTEREST.

The study is one of the few phase III clinical trials to directly compare the efficacy of docetaxel with an EGFR tyrosine kinase inhibitor. The analysis included 1,433 patients who had not responded to previous chemotherapy, recruited from 149 centers in 24 countries between March 1 2004 and February 17 2006.

The most frequent side effects of gefitinib were acne, rash and diarrhea. Just 4 percent of patients taking the drug experienced serious adverse events – a similar rate to that seen at NCCS, where Toh estimates that “less than 5 percent” of patients on gefitinib develop side effects to the point where they have to stop therapy.

For docetaxel the most common side effects in the trial were hematological toxic effects, hair loss and weakness. Serious adverse events occurred in 18 percent of patients in this group.

The non-inferiority of gefitinib was demonstrated by the median overall survival, which was 7.7 months in patients taking the drug compared to 8 months for those taking docetaxel. One-year survival rates were 32 and 34 percent in the respective groups.

Gefitinib patients were twice as likely to have a “sustained and clinically relevant improvement in quality of life,” as measured by the Functional Assessment of Cancer Therapy-Lung score (odds ratio 1.99; P<0.0001).>

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*Iressa NSCLC Trial Evaluating REsponse and Survival versus Taxotere

Wealthy elderly more susceptible to air pollution

Medical Tribune January 2009 P12

David Brill

Abandoning your condo and moving to a poorer neighborhood might be good for your health if you live in a developing country, new research suggests.

The study of 7,358 elderly residents of Chinese cities found that those who lived in the wealthiest areas were more susceptible to the damaging effects of air pollution than those living in less prosperous parts of town.

An equivalent increase in pollution levels was linked to worse cognitive function, poorer self-reported health and greater difficulties with activities of daily living among residents of the highest GDP neighborhoods compared with the lowest.

The findings are at odds with research from Western populations which has found that the poorer the neighborhood, the greater the exposure to air pollution and the worse its effects on health. [Environ Health Perspect 2003 Dec;111(16):1861-70]

The new study shows that the relationship between air pollution and health in developing economies is more complex than previously thought, one of the researchers said.

“People tend to think in developing countries that when there’s more development there should be higher pollution but that is not what we’ve found. We showed that there is no clear correlation between the economic development level and the air pollution level,” said Rongjun Sun, an associate professor of sociology at Cleveland State University, US.

“The major message of our paper is that air pollution does have a dramatic impact on the health of the elderly but it’s not as simple as people imagine. I think when we look at this we will have to take a longer-term perspective.”

The researchers used data from the third wave of the Chinese Longitudinal Health Longevity Survey, conducted in 2002. Over-65s from 735 districts in 171 cities were included in the analysis. [Am J Epidemiol 2008 Dec 1;168(11):1311-8]

The reasons for the apparent discrepancy between East and West are not clear but may reflect differences in the usage of natural resources at the different stages of economic development, suggested Sun.

History suggests that as countries develop they move from industrial economies to more service-based economies, eventually becoming richer and reaching the position where they can begin to address the quality of the environment, he added.

Managing diabetic retinopathy in primary care

Medical Tribune January 2009 P14-15

Diabetic retinopathy is a leading cause of visual loss in Asia and one of the major chronic eye diseases handled by GPs. Left untreated, it can result in permanent blindness from neovascular glaucoma or tractional retinal detachment arising from proliferative diabetic retinopathy.

The condition is expected to become more common as the prevalence of diabetes continues to rise in Asia.

A recent study found that 38.1 percent of diabetics who were referred for retinal assessment as part of a nationwide screening program in Singapore had retinopathy. [Ann Acad Med Singapore 2008 Sep;37(9):753-9] The Singapore Malay Eye Study, meanwhile, demonstrated a retinopathy prevalence of 35 percent among diabetics of Malay ethnicity, of whom 9 percent had vision-threatening retinopathy. [Ophthalmology 2008 Nov:115(11):1869-1875]. This high rate of diabetics suffering from retinopathy is consistent worldwide. The proportion of type 2 diabetics having retinopathy has been reported to be 40.3 percent in the US, 35 percent in Taiwan and 10.5 – 26.2 percent in India.

Pathogenesis

Diabetic retinopathy is a highly specific microvascular complication of both type 1 and type 2 diabetes mellitus, resulting from progressive damage to the retinal blood vessels caused by hyperglycemia in the blood. The condition is caused by increased vascular permeability at onset, leading to fluid accumulation in the retina. With time, there is vascular shutdown, causing ischemia of the retina. This leads to retinal neovascularization at the disc or elsewhere, vitreous hemorrhages, fibro-proliferative changes and retinal detachment. Neovascular glaucoma can also develop. The prevalence is strongly related to the duration of diabetes mellitus, and most diabetic patients will develop retinopathy with time.

See the sidebar for a classification of the different disease stages.

Screening

As patients with sight-threatening retinopathy may not show any symptoms, fundal screening of diabetic patients is crucial in helping to identify those at risk of developing complications that will impact on their vision and quality of life. The importance of regular screening for diabetics, therefore, cannot be understated.

All diabetic patients should be screened for retinopathy on an annual basis at the very least, beginning from the point of diagnosis. Those who are at high risk for developing retinopathy need to be monitored more closely and should be screened at least twice yearly. The major risk factors to consider are hypertension, high cholesterol, smoking, patient’s age, duration of diabetes and a history of poor glycemic control. The Singapore Malay Eye Study also found that a history of stroke, cardiovascular disease or chronic kidney disease was associated with vision-threatening retinopathy.

Female diabetics who are planning to conceive should be screened prior to conception and again in the first trimester. The regularity of follow-up should then be determined based on the results of the first trimester examination.

For patients with established retinopathy, the timing of follow up examinations depends on their disease status.

Physicians who are involved in providing diabetic care have a pivotal role in ensuring that patients are screened. This can be performed via fundal photography, indirect fundoscopy or direct ophthalmoscopy through a dilated pupil.

While the need for regular screening is well accepted by the medical community, it is an unfortunate reality that patients are often not screened as frequently as they should be. Many patients do not understand the progressive nature of the disease process, mistakenly believing that if there is nothing wrong with their vision, then they do not need to see an eye doctor. Many appointments are missed as a result, and the early signs of diabetic retinopathy can often go undetected. Accessibility can also be a problem, particularly in rural areas, and can also contribute to the missing of screening appointments.

We must educate patients on the importance of these check-ups, and help them to understand that by the time they discover they have developed visual problems, it may already be too late to treat them. GPs can also help patients to attend their screening appointments by checking regularly whether they are compliant with their schedules, reminding them about upcoming
visits and making sure that they are referred to the most appropriate and convenient center.

Practice guidelines

The most widely-used guidelines on diabetic retinopathy come from the American Academy of
Ophthalmology. These have been incorporated into clinical practice guidelines on the management of diabetic retinopathy from Singapore’s Ministry of Health, published in January 2004, which help GPs plan their management and screening schedules for their patients. Diabetic retinopathy guidelines are also available from the Academy of Medicine of Malaysia.

Treatment

Laser treatment is the major therapy for diabetic retinopathy but can lead to long-term side effects such as a reduced field of vision.

There is now a considerable weight of data showing the benefits of good glycemic control on
retinopathy outcomes. The Diabetes Control and Complications Trial (DCCT) found that an intensive strategy reduced the risk of developing retinopathy by 76 percent and slowed disease progression by 54 percent. [N Engl J Med 1993 Sep 30;329(14):977-86] Recent data from the United Kingdom Prospective Diabetes Study (UKPDS) show that the benefits of intensive glucose control extended long beyond the trial intervention, with a 24 percent risk reduction for microvascular disease noted 10 years after the conclusion of the study. [N Engl J Med 2008 Oct 9;359(15):1577-89]

Tight blood pressure control is also important. The original UKPDS data demonstrated a 47 percent reduction in the risk of having decreased vision in both eyes, after 9 years of follow up. [BMJ 1998 Sep 12;317(7160):703-13] The 2008 data showed that the benefits disappeared once treatment was withdrawn, suggesting that blood pressure control needs to be maintained in order to continue to derive the maximum benefits. [N Engl J Med 2008 Oct 9;359(15):1565-76]

Medication adherence is often a major obstacle in achieving these targets. GPs should continue to ensure that patients are well-educated on the importance of taking their drugs, making them aware that failure to do so increases their risk of retinopathy. Regular HbA1c and blood pressure tests should be carried out to monitor progress, and medication adjusted accordingly.

Disease management tools

In October 2006, the Ministry of Health in Singapore launched the Chronic Disease Management Program, focusing initially on diabetes and then on hypertension, dyslipidemia
and stroke. The plan is to transform management of these diseases by forming an effective
partnership among GPs, medical specialists and patients through effective information flow within the partnership throughout the healthcare continuum. The program aims to equip GPs with a better understanding of patients’ medical histories through up-to-date electronic records and, in turn, reduce medical costs and enable the provision of quality healthcare services customized to individual requirements.

This integrated clinic management system provides GPs with a complete system to manage their patients and clinic operations. Critical clinical indicators are stored, enabling GPs to use this data to track the progress of their patients. Clinical decision support tools are also built into the system to help GPs plan effectively and communicate care plans to their patients. In this way, schedules for retinopathy screening can be built into the patients’ management plan, helping doctors keep to the intended schedules.

Conclusion

Regular screening is the cornerstone of detecting, monitoring and managing diabetic retinopathy and should be arranged from the very point of diagnosis. Patients should be educated about the importance of screening and followed up at all stages to ensure compliance to their schedules. Good glycemic and blood pressure control are also of vital importance in preventing the development and progression of this potentially sight-threatening condition. It is strongly recommended that the organization of retinopathy screening be primarily the responsibility of the GPs, who will then refer all patients with retinopathy or media opacity to an ophthalmologist for more specialized treatment.

Online Resources:

The American Academy of Ophthalmology guidelines:

www.guideline.gov/summary/summary.aspx?doc_id=4350

Office BP not prognostic for resistant hypertension

Medical Tribune January 2009 P16
David Brill

Office-based blood pressure (BP) measurements offer “no prognostic value” for patients with resistant hypertension, a recent study has concluded.


Ambulatory BPs – both systolic and diastolic – were predictors of future cardiovascular morbidity and mortality whereas neither measurement was a significant indicator when recorded in the office, the researchers found.

The study, which followed up 556 outpatients for a median of 4.8 years, also showed that nighttime ambulatory BP was superior to daytime as a prognostic indicator, suggesting that these time periods should be analyzed seperately to give the best assessment of a patient’s cardiovascular risk.

It is only the second prospective study to assess the different BP monitoring strategies in resistant hypertensive patients, according to the researchers, who are based at the Federal University of Rio de Janeiro, Brazil. They note that the superiority of ambulatory BP “is not generally accepted,” despite several studies showing that it offers better cardiovascular risk prediction than office BP in various other patient populations. [Arch Intern Med 2008 Nov 24;168(21):2340-6]

Dr. Chai Ping, a Singapore-based specialist, said that the study should encourage physicians to use ambulatory BP more often for patients with resistant hypertension.

“In the initial evaluation of a patient with elevated office BP despite three or more medications, ambulatory BP monitoring should be performed to confirm that the BP is truly elevated and not a ‘white-coat’ effect,” he said.

“This paper also tells us that suboptimal BP control, as has been known for more than 4 decades now, confers a worse prognosis for hypertensive patients, so every effort must be made to control BP to the targets as recommended by current clinical practice guidelines,” added Chai, who is clinical director of the noninvasive cardiac laboratory at the National University Heart Centre Singapore (NUHCS).

The patients included in the study met standard criteria for resistant hypertension. The mean hypertension duration at enrollment was 18 years. Some patients were followed up for as long as 9 years.

A total of 109 patients (19.6 percent) reached the study’s primary endpoint – a composite of fatal and non-fatal cardiovascular events.

Patients with a one standard deviation increase in nighttime systolic BP at baseline had a 38 percent increased risk of reaching this endpoint following multivariate adjustment (hazard ratio [HR] 1.38), while an equivalent increase in nighttime diastolic BP yielded a 36 percent increase in risk (adjusted HR 1.36; P<0.05 for both).

The only significant predictor of death was a so-called “true” diagnosis of resistant hypertension, based on ambulatory BP monitoring rather than office-based measurement. This diagnosis was associated with a twofold increase in the risk of all-cause mortality (adjusted HR 2.00; P<0.05).

Chai estimates that up to a quarter of patients being followed up at the NUHCS have resistant hypertension. He said that he presently uses both forms of BP measurement but noted that not all hypertensive patients require ambulatory BP monitoring.

The results of the study cannot be generalized to all patients with hypertension, he added.

The meteoric rise of HIV

Healthy Times December 2008
David Brill (aka David Wise)

December 1 is World Aids Day. To mark the event medical journalist David Wise looks at the humble origins of this global killer and its journey from an isolated outbreak to a worldwide pandemic.

Léopoldville may not be a familiar name to many, yet the city played host to one of the defining events of mankind’s recent history. The former Belgian colonial capital – now known as Kinshasa, Democratic Republic of the Congo – is thought to be the birthplace of HIV, the virus responsible for the AIDS pandemic which is currently affecting over 33 million people worldwide.

The precise origins of HIV remain a mystery but new research allows scientists to paint a more detailed picture than ever before. They now believe that the virus first reached humans in Léopoldville around 100 years ago, where it found a foothold among the booming population of the newly-founded city.

It is likely that HIV spread slowly at first, experts say, while the fact that symptoms differ widely between individuals may have prevented it from being recognized for many years. It was not until 1981 that French scientists Françoise Barré-Sinoussi and Luc Montagnier formally identified the virus – a discovery that was honored this year with the award of the Nobel Prize for medicine.

The true beginning of the story, however, begins not with humans but with our primate cousins. Today there are several different types of HIV, each of which may have its own tale to tell, but the particular strain responsible for the current pandemic seems to have evolved from a virus which naturally infects chimpanzees. In 2006 researchers announced that they had found this HIV forefather – the Simian Immunodeficiency Virus (SIV) – among wild chimps living in southeast Cameroon.

Most scientists accept that SIV became HIV, but how it first crossed the species barrier is largely a matter for speculation, according to Professor Robin Weiss, an HIV expert from University College London, UK.

“The most likely explanation is that it began with the butchering of apes,” he explains. “There was blood and splintered bones and goodness knows what lying around, and then the virus got transferred into small cuts or abrasions on the skin. If you wanted to be lurid you could raise a King Kong scenario of sex with a great ape but I think that’s a bit sensational myself.”

The first known case of HIV comes from a preserved tissue specimen dating back to 1959, which was found in the archives at the University of Kinshasa. In 2000, Betty Korber and her team at the Los Alamos National Laboratory, US, published an important research paper analyzing the genetic sequence of this virus. Their calculations, they said, suggested that the virus had likely been born around 1931 – back when Kinshasa was still known as Léopoldville.

But this information begged an important question which has only recently been answered: how did the slaughtering of chimps in southeastern Cameroon lead to the infection of humans in Léopoldville some 700km away?

The answer was provided in October of this year when Michael Worobey and his colleagues from the University of Arizona, writing in the journal Nature, announced that they had found another early HIV specimen lurking in the archives at Kinshasa. The tissue sample – a lymph node taken from an adult woman – had been fixed in preservative back in 1960.

This discovery enabled the team to compare the virus with Korber’s specimen from 1959. By looking at genetic differences between the two samples and tracing their family trees backwards, they established that the viruses must have shared a common ancestor between 1884 and 1924. Their best estimate puts the birth of HIV at 1908 – some 23 years earlier than previously thought.

Worobey’s team went one step further and placed their genetic studies alongside demographic data on the growth of cities in west-central Africa. They found that their estimate of 1908 coincided with a period of population boom in Léopoldville, suggesting that growth of the city provided the necessary kick-start for HIV to spread. Before 1900, there was not one settlement in the area with more than 10,000 people, but by 1910 Léopoldville had established itself as the region’s major city.

As the colonial outpost grew, so it continued to flourish as an administrative and trading center. With transportation at the time largely restricted to boats, Léopoldville found itself ideally situated on the Congo River – the final destination of many of the tributaries that run through the forests of Cameroon. The identity of the person that first contracted SIV may remain a mystery, but their arrival in the city now seems the likely trigger for the modern-day AIDS pandemic.

This newfound understanding of where HIV came from can provide important insights into the evolution of future pandemics, according to Weiss.

“These examples of particular viruses help to inform our general thinking about the origins of infections that come from animals. And for sure we’ve haven’t seen the last one – there’ll be some other disease like SARS or something that we haven’t even thought about today,” he says.
“And looking back at HIV in its very humble, small beginnings… who would have guessed that this would turn out to be the major killer at the end of the 20th century?”

JUPITER shows statin benefits for low-risk patients

Medical Tribune December 2008 P1 & 13

David Brill

Rosuvastatin can dramatically reduce the risk of death and major cardiovascular events among apparently healthy people, the highly-anticipated results of the JUPITER* study show.

The findings raise important questions about the indications of statins for primary prevention and should prompt a reassessment of current guidelines on risk assessment, one expert said.

JUPITER comprised 17,802 overtly healthy people with normal LDL cholesterol but elevated levels of high sensitivity C-reactive protein (hsCRP) – a group not currently indicated for statin treatment.

A 44 percent reduction in the incidence of the primary endpoint – comprising myocardial infarction (MI), stroke, cardiovascular death, arterial revascularization or unstable angina – was seen among those taking the drug compared to those on placebo (hazard ratio 0.56; P less than 0.00001).

Just 25 people would need to be treated with rosuvastatin to prevent one vascular event over a 5-year period, the researchers said.

The benefits of treatment were such that the trial was stopped a median of 1.9 years into the intended 4 year follow-up period.

"Despite evaluating a population with lipid levels widely considered to be optimal in almost all of our current guidelines, the relative benefit observed in JUPITER was greater than in almost all prior statin trials," said Professor Paul Ridker, the study’s principal investigator who presented the findings at a press conference during the recent annual Scientific Sessions of the American Heart Association.

"I think this is extremely reassuring for the statins as a class, and hopefully for the public at large who have been concerned about mortality benefits in this setting," he said.

Rosuvastatin reduced all-cause mortality risk by 20 percent and MI, stroke or cardiovascular death risk by 47 percent compared to placebo (hazard ratios 0.80 and 0.53; P=0.02 and P less than 0.00001, p=0.01).

The risk reductions were consistent across all subgroups regardless of gender, age, ethnicity, smoking status, BMI and Framingham risk score.

Statin therapy appears to have been safe, with no significant difference in serious adverse event rates between the groups. There was, however, an increase in the rate of physician-reported diabetes: 270 cases were recorded in the statin group and 216 in the placebo group (P=0.01).

Professor Andrew Tonkin, head of the cardiovascular research unit at Monash University, Melbourne, Australia, described the reduction in cardiovascular events in JUPITER as “extremely important.”

“I think that there will need to be a review of the guidelines for where CRP sits in risk assessment,” he said, adding that more information, such as the absolute risk reductions in subgroups and the cost effectiveness of treatment, is critically needed in order to establish the role of the marker as a screening tool for primary prevention.

Dr. Timothy Gardner, president of the American Heart Association, noted that the mechanisms for the risk reductions seen in JUPITER remain unclear.

“Statins lower both LDL cholesterol and hsCRP. Thus the findings presented today cannot determine whether lowering cholesterol, reducing inflammation, or a combination of both is responsible for the effects seen in this paper,” he said.

JUPITER, which was concurrently published in The New England Journal of Medicine, included men aged 50 or older and women aged 60 or older who had LDL cholesterol levels below 130mg/dl and hsCRP levels of 2.0mg/l or higher. Participants were non-diabetics with no history of cardiovascular disease. [2008 Nov 9; Epub ahead of print]

Rosuvastatin treatment (20mg daily) reduced LDL cholesterol levels by 50 percent and hsCRP by 37 percent.

Ridker, of Harvard Medical School, Boston, US, acknowledged that the study was too short to fully assess long-term safety, but noted that there is a large amount of data on statins as a whole and that they have been found to be “remarkably safe.” Despite the early conclusion, over 1,000 people in JUPITER were followed up for more than 4 years, he added.

“These drugs as a class are extraordinary. We want to give out a message that we want to continue with diet, exercise and smoking cessation but now we have very overwhelming evidence that this class of drugs, this method of lowering these surrogates [LDL cholesterol and hsCRP], fixes hard endpoints,” he said.

The JUPITER trial was supported by AstraZeneca.

*Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin

ADA, EASD offer practical new guidance on diabetes treatment

Medical Tribune December 2008 P4
David Brill

An updated treatment algorithm has been released which promises to help guide primary care physicians through the ever-expanding field of treatments for type 2 diabetes.

The consensus statement, produced jointly by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), places a strong emphasis on early treatment and the maintenance of HbA1c levels below 7 percent.

Metformin therapy plus lifestyle intervention is recommended from diagnosis for all patients, with further medications to be added promptly if targets are not achieved.

The statement also makes new differentiations within drug class
– advocating pioglitazone over rosiglitazone and dropping glybenclamide and chlorpropamide from the list of recommended sulfonylureas.

"We’ve seen absolutely that if you do not keep glucose levels within reasonable bounds you will reap a harvest of microvascular disease," said Professor Rury Holman, one of the authors of the algorithm.

"The tide is changing. The view that complications are inevitable is no longer true. They will occur even in the best controlled-people but the risk can be substantially reduced, and therefore I think we have a duty of care to minimize HbA1c to the extent that we can," he said.

Holman, head of the Diabetes Trials Unit at The Oxford Centre for Diabetes, Endocrinology and Metabolism, UK, said that the new algorithm is "not a prescription" to be followed in all cases but rather an evidence-based starting point for primary care doctors, who should still seek specialist advice where appropriate.

He also stressed the need to adopt a more cautious approach to HbA1c lowering in patients with a long-standing history of disease, noting that physicians should weigh up the relative risks and benefits before attempting to push HbA1c levels below 7 percent.

The latest version of the ADA/ EASD treatment algorithm, first issued in 2006, was published online recently in the journals Diabetes Care and Diabetologia. The document will continue to be updated as and when new data become available, Holman said.

For cases where the initial metformin approach is unsuccessful, the algorithm divides the subsequent intensification of therapy into two tiers according to how well validated the medications are considered to be. Tier 1 sees the addition of either sulfonylurea or basal insulin, progressing to initiation or intensification of insulin therapy. Tier 2 recommends pioglitazone or the glucagon-like peptide-1 agonist exenatide, before moving on to sulfonylurea or basal insulin.

Besides the algorithm, the consensus statement also contains a literature review on the relative merits of the different medications, and guidance on the titration of metformin and the initiation and adjustment of insulin regimens.

Dr. Kevin Tan, vice president of the Diabetic Society of Singapore, agreed that doctors now have a duty to initiate early, intensive glycemic control and said that incorporating the new algorithm would help them to focus on the older, better-established drugs and view the newer options as alternatives to be used where necessary.