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.