Thursday, January 24, 2008

NSAIDs, Acetaminophen Equivalent in Relieving Low Back Pain

By Michael Smith
ROTTERDAM, The Netherlands, Jan. 23 -- For lower back pain, the old standby acetaminophen appears to be as effective for pain relief as nonsteroidal anti-inflammatory drugs (NSAIDs), researchers here said.
A meta-analysis of 65 studies of NSAIDS for lower back pain, with or without sciatica, showed the drugs are more effective than placebo but roughly equivalent to acetaminophen, according to a systematic review published in the first 2008 issue of The Cochrane Library.
But NSAIDs have significantly more side effects -- mainly gastrointestinal -- than acetaminophen, with a relative risk of 1.76 (with a 95% confidence interval from 1.12 to 2.76), the researchers found.
The findings support guidelines that suggest NSAIDs be used only after acetaminophen (also known in Europe as paracetamol) has been tried, "since there are fewer side effects with paracetamol," said lead author Pepijn Roelofs, a doctoral student at Erasmus University in Rotterdam, Holland, and colleagues.
The report is an undated version of a review first published in 2002. It includes 15 new studies, the researchers said. Of the 65 evaluated studies, which enrolled 11,237 patients, 28 (or 42%) were considered high quality.
The 65 studies compared NSAIDs to placebo, acetaminophen, muscle relaxants, and other drugs, non-drug treatments, and other NSAIDs, the researchers said.
They looked at 11 studies comparing NSAIDS to placebo in acute low back pain and four in chronic pain.
For acute pain, the studies were heterogeneous, but there was enough information to conclude that NSAIDs were more effective than placebo, with a pooled relative risk for global improvement after one week of 1.19, with a 95% confidence interval from 1.07 to 1.33.
The effect sizes seen in the individual studies were also small, the researchers noted.
On the other hand, there was no significant difference if the patients were suffering from sciatica.
Side effects were more common in patients getting NSAIDs, with a pooled relative risk of 1.35 (with a 95% confidence interval from 1.09 to 1.68).
For chronic pain, NSAIDs also significantly reduced pain (P<0.00001), but had significantly more side effects (pooled relative risk of 1.24, with a 95% confidence interval from 1.07 to 1.43).
Only seven studies compared one or more types of NSAIDs with acetaminophen, the researchers found and they provide "moderate evidence" that the two forms of medication are equivalent in reducing acute low back pain, the researchers said.
But, they said, there's "limited evidence" -- a single study -- showing NSAIDs to be more effective in treating chronic pain.
The analysis also found:
"Moderate evidence" that NSAIDs are no more effective than other drugs for acute low back pain.
"Strong evidence" that various types of NSAIDs, including the controversial cyclooxygenase-2 inhibitors (COX-2), are equally effective for acute low back pain.
The COX-2 NSAIDs, in these studies, had significantly fewer side effects than traditional NSAIDs. The pooled relative risk was 0.83, with a 95% confidence interval from 0.70 to 0.99.
The researchers noted that the COX-2 inhibitors have been enveloped with controversy over long-term cardiovascular side effects.
"It might well be," they argued, "that in the majority of patients with low back pain, the intake is of short duration and might not reach the level associated with increased cardiovascular risks."
The benefit of the medications "varies from individual to individual," said Jon Levine, M.D., of the University of California San Francisco, who was not affiliated with the review.
"If one NSAID does not work, you can try another," he said in a statement. "This is often a very empirical situation. If it takes care of the pain, wouldn't you take it?"
The study was supported by the Dutch Health Insurance Board.
The researchers did not report any potential financial conflicts.
Primary source: Cochrane Database of Systematic ReviewsSource reference:Roelofs PDDM, et al "Non-steroidal anti-inflammatory drugs for low back pain" Cochrane Database of Systematic Reviews 2008; Issue 1: DOI: 10.1002/14651858.CD000396.pub3.
Herbal Remedy Deemed Safe and Seemingly Effective in Heart Failure

By John Gever
EXETER, England, Jan. 23 -- Hawthorn extract is safe and has significant benefits for patients with congestive heart failure, according to a meta-analysis here.
Data from 14 randomized placebo-controlled trials involving 1,110 patients indicated that the herbal remedy significantly improved maximal workload, exercise tolerance, pressure-heart rate product, and symptoms such as shortness of breath and fatigue, reported Max Pittler, M.D., Ph.D., of the University of Exeter, and colleagues in a Cochrane review.
In most of the trials, patients were taking conventional cardiac medications such as diuretics, ACE inhibitors, and calcium antagonists along with the study medications. Concomitant medications were not mentioned in the other studies.
As a result, Dr. Pittler and colleagues wrote, it cannot be concluded definitively that the herbal remedy alone accounted for the results. On the other hand, it appears that hawthorn extract can be combined safely with conventional heart drugs.
The Cochrane analysis did not include results from SPICE, a large placebo-controlled trial presented at a major cardiology meeting last year that found equivocal benefits at best for hawthorn extract.
That still-unpublished study involved more than twice as many patients as all the trials included in the Cochrane study. SPICE found no difference after two years of treatment in a composite endpoint of cardiac events, including death, nonfatal myocardial infarction, and heart failure progression.
Dr. Pittler and colleagues included only studies published in medical journals through June 2006, thereby excluding the SPICE results.
Extracts made from leaves, flowers, and fruits of hawthorn, a shrub with the Latin name Crataegus laevigata, and also known as whitethorn, are a staple of alternative and complementary medicine. Hawthorn extract has been touted as a treatment for heart failure and hypertension.
Most of the trials included in the Cochrane analysi,s as well as SPICE, used a standardized product called WS-1442, with the others studying another product known as LI132. Doses ranged from 160 mg to 1,800 mg daily.
Maximal workload was the most frequent outcome measure used in the 14 included studies. Pooled data from trials involving 380 patients showed that hawthorn extract increased maximal workload by a weighted mean difference of 5.35 watts (95% CI: 0.71 to 10.00, P<0.02).
For pressure-heart rate product, pooled data from five trials and 264 patients found a weighted mean decrease of -19.22 mm Hg/min (95% CI: -30.46 to -7.98).
Exercise tolerance improved by a weighted mean difference of 122.76 watt-min (95% CI: 32.74 to 212.78) in trials involving 98 patients.
Two studies with 239 patients found a weighted mean decrease of -5.47 points (95% CI: -8.68 to -2.26) in dyspnea and fatigue scores.
Only one trial, involving 113 patients, tested for six-minute walk distance. It found no significant difference.
Dr. Pittler and colleagues sought data on mortality and cardiac events, but the included trials reported no analyzable data for these outcomes.
The most common adverse events with hawthorn extracts were dizziness and gastrointestinal complaints, both of which affected fewer than 10 patients in the included trials.
The researchers noted that post-marketing surveillance studies not included in their formal analysis also have found low rates for adverse effects. One study of 3,664 patients reported event rates of 1.3%.
"Our results suggest that, compared with placebo, hawthorn extract increases the maximal workload in patients with chronic heart failure," Dr. Pittler and colleagues wrote. "This conclusion, however, is based on small numbers of studies and patients. Nevertheless, the secondary outcome measures support the findings and suggest that hawthorn extract is superior to placebo as an adjunctive treatment for patients with chronic heart failure."
They added that future investigations are needed to determine whether hawthorn extract treatment affects the prognosis of heart failure.
They pointed out that, as with any systematic review, they may have excluded some relevant studies. Methodologies and degree of rigor varied among the included trials as well, the researchers said.
Gregg Fonarow, M.D., director of UCLA's heart failure program, said he agreed with Dr. Pittler and his group that hawthorn extract is safe for heart failure patients. He said the review "does indeed demonstrate that it is not a harmful therapy."
But he disputed the group's conclusion that hawthorn is superior to placebo, citing the SPICE results reported last March at the American College of Cardiology's annual meeting in New Orleans.
That study, conducted mainly in eastern Europe, tested WS-1442 against placebo in 2,618 heart failure patients. Christopher Holubarsch, M.D., of Median Kliniken Hospitals in Bad Krozingen, Germany, reported no difference after two years of treatment in the primary outcome measure. It was a composite of cardiac events including death, nonfatal myocardial infarction, and heart failure progression.
Significant reductions in relative risk for cardiac death in patients receiving hawthorn extract were seen at six and 18 months, but not at 12 or 24 months, according to the report.
Dr. Fonarow said these results impressed him more than the Cochrane review. He said hawthorn "is not particularly helpful" and would not recommend it for patients.
"It's naturally attractive to think there is something over the counter or naturally occurring that may help improve outcome. Unfortunately, we've not been able to identify that so far," he said.
The review was funded by the Videns-og forsknings-center for alternativ behandling (Denmark).
No financial conflicts of interest were reported.
Primary source: Cochrane Database of Systematic ReviewsSource reference:Pittler M, et al "Hawthorn extract for treating chronic heart failure" Cochrane Database of Systematic Reviews 2008; Issue 1: DOI: 10.1002/14651858.CD005312.pub2.
Single Tool Predicts Global and Specific Cardiovascular Risks

By Charles Bankhead
BOSTON, Jan. 23 -- A patient's global cardiovascular disease risk can be predicted accurately by an office-friendly algorithm, according to investigators here.
What's more, simple adjustments to the general algorithm allow accurate prediction of a patient's risk for each cardiovascular disease component -- coronary disease, cerebrovascular disease, peripheral arterial disease, and heart failure.
So said Ralph B. D'Agostino, Sr., Ph.D., of Boston University, and colleagues online in Circulation: Journal of the American Heart Association, in a Framingham study-based report slated for the Feb. 12 print issue.
Traditional cardiovascular disease risk factors proved to be highly significant predictors of cardiovascular disease risk (P<0.0001), and the general algorithm demonstrated good discrimination for men and women, they found.
"Individuals with a high overall cardiovascular disease risk require more aggressive risk factor modification," said Dr. D'Agostino and colleagues. "The goal of therapy for cholesterol disorders, diabetes, and hypertension should be linked to the global cardiovascular disease risk."
Use of validated cardiovascular disease risk prediction algorithms has lagged in primary care, in part because of the sheer number of algorithms, each targeted toward predicting a patient's risk for an individual cardiovascular disease event, the authors said.
So they set out to develop a single multivariable risk assessment tool that would allow physicians to identify patients with a high risk for any type of cardiovascular disease event, using measurements that are readily available in an office or clinic.
The resulting algorithm was derived from data on 8,491 Framingham study participants followed for 12 years. The patients were 30 to 74 years old at their initial examination and were free of cardiovascular disease.
Investigators developed sex-specific multivariable risk functions that incorporated several readily assessable cardiovascular disease risk factors:
Patient age
Total cholesterol and HDL
Systolic blood pressure
Treatment for hypertension
Smoking status
Diabetes status
During follow-up, 1,174 participants developed a first cardiovascular disease event, which translated into an occurrence rate of 10.08% for women and 18.09% for men. For predicting global cardiovascular disease risk, the algorithm demonstrated good accuracy for men and women, as reflected by c-statistics of 0.762 and 0.793, respectively. In contrast, an earlier Framingham risk algorithm yielded lower c-statistics of 0.756 for men and 0.778 for women.
Comparison of the two algorithms resulted in a "net reclassification improvement from using the new model that was statistically significant for men [P<0.001] and women [P=0.003]," the authors said.
To determine a patient's risk for individual cardiovascular disease events, the global risk score was calculated and then multiplied by the proportion of total cardiovascular disease events represented by the specific event. For example, a woman's risk for coronary heart disease events was determined by multiplying her global risk score by 0.61, the proportion of first cardiovascular disease events that were coronary heart disease events.
Discussing the clinical implications and potential utility of the algorithm, the authors noted that "a multivariable risk formulation for global cardiovascular disease made up of standard risk factors is particularly relevant for primary prevention of atherosclerotic cardiovascular disease because it is intuitive that measures taken to prevent any one cardiovascular disease outcome can be expected to also prevent risk of the other cardiovascular disease outcomes."
"Therefore, use of a general cardiovascular disease risk score is an attractive option in office-based primary care practices," they continued. "Serial assessment of global cardiovascular disease risk could be used to monitor progress of patients on treatment and improvement in their multivariable risk scores."
They also pointed out that "other risk factors not included in the general risk profile must be taken into account in evaluating risk and selecting the most efficacious treatment. These include abdominal obesity, ECG evidence of left ventricular hypertrophy, indications of insulin resistance, triglycerides, and a strong family history of premature cardiovascular disease. Obesity is not included because its influence is largely attributable to its promotion of insulin resistance and its attendant cardiovascular disease risk factors."
In acknowledging limitations of the study, the authors noted that the algorithm did not include all cardiovascular risk factors. They also acknowledged that the algorithm requires validation in other populations.
Dr. D'Agostino has served as a consultant or adviser for Sanofi and Pfizer.
Primary source: CirculationSource reference:D'Agostino RB, et al "General cardiovascular risk profile for use in primary care: the Framingham heart study" Circulation 2008; 117: DOI: 10.1161/CIRCULATIONAHA.107.699579.
Questioning the Importance of LDL Cholesterol: The ENHANCE Fallout

Michael O'Riordan

The debate surrounding the ENHANCE trial took a bit of a twist this past week when attention turned to the LDL-cholesterol hypothesis, with some experts arguing that lowering LDL cholesterol to prevent clinical events is an unsophisticated premise and that other factors beyond lowering LDL cholesterol are involved. Other reports openly questioned whether this latest evidence suggests it might not be important to reduce cholesterol levels.
"The idea that you’re just going to lower LDL and people are going to get better, that’s too simplistic, much too simplistic," Dr Eric Topol (Scripps Translational Science Institute, La Jolla, CA) told the New York Times last week [1].
Experts say, however, that this is not the dismissal of decades of research, including numerous studies in the past few years adding evidence to the "lower-is-better" cholesterol hypothesis. With many of those trials, researchers used higher and higher doses of statins to drive down cholesterol levels, all with the intention of further reducing clinical events. Instead, some say that how cholesterol is lowered is as important as how much.
"The message for me is not that lowering LDL cholesterol doesn't work to prevent disease progression or to prevent clinical events," Dr Steven Nissen (Cleveland Clinic, OH) told heartwire. "The important thing to remember is how the cholesterol levels are lowered. Statins do a lot more than reduce LDL cholesterol. They also increase HDL cholesterol, decrease triglycerides, and decrease C-reactive protein levels. Ezetimibe doesn’t do any of these things."
The temple of LDL cholesterol
In his most recent video post on's TopoLog, entitled "Temple of the LDL cholesterol," Topol called the ENHANCE results surprising but noted that the ezetimibe/simvastatin combination would not even have met the criteria for noninferiority on the primary end point of carotid intima media thickness (IMT).
In terms of what this study means for LDL cholesterol and reducing events in cardiovascular medicine, Topol referenced a 1999 study by Dr Frans Van de Werf (University of Leuven, Belgium) and colleagues that showed that LDL had no predictive value but that oxidized LDL cholesterol was predictive of acute coronary syndrome and MI.
"One of the problems we may indeed be suffering is that we consider all LDL cholesterol the same," said Topol. "We know that the oxidized form is particularly noxious and proinflammatory. We don't know, for example, how different ways of lowering LDL cholesterol, such as with ezetimibe or statins, affect subspecies of LDL cholesterol, and we certainly have no knowledge about ezetimibe's reduction of events."
Is lowering LDL cholesterol important?
With the release of ENHANCE, a study showing that reductions in LDL cholesterol did not translate into improvements in atherosclerosis as measured by carotid IMT, as well as torcetrapib data published last year, questions have been raised about whether or not it is important to reduce LDL-cholesterol levels at all.
Some clinicians, in fact, are quite candid in their interpretation of the newly presented data. Dr Rodney Hayward (University of Michigan, Ann Arbor), for example, told BusinessWeek that the "current evidence supports ignoring LDL cholesterol altogether. [2]"
In case you've been under a rock . . .
The ENHANCE study captured the attention of clinical cardiology, the business world, and the media this past week when the results of the long-awaited and controversial ENHANCE study were presented. Investigators presented data showing no benefit of the combination of ezetimibe (Zetia, Merck/Schering-Plough Pharmaceuticals) and simvastatin (sold together as Vytorin, Merck/Schering-Plough Pharmaceuticals) over simvastatin alone.
ENHANCE, with lead investigator Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands), was conducted in 720 patients with heterozygous familial hypercholesterolemia (FH) and showed no significant difference in the primary end point--mean change in IMT measured at three sites in the carotid arteries--between patients treated with ezetimibe/simvastatin 10/80 mg and patients treated with simvastatin 80 mg alone over a two-year period.
There was also no statistically significant difference between the treatment groups for each of the components of the primary end point, including the common carotid artery. Key secondary imaging end points showed no statistical difference between treatment groups.
Commenting on the current climate following the release of the ENHANCE data, Dr Patrick McBride (University of Wisconsin Medical School, Madison) told heartwire that the LDL hypothesis is irrefutable.
"Anytime you can lower LDL-cholesterol levels safely, you are going to see reductions in the risk of clinical events," he said. "In any of the previously published cholesterol studies, there is always a decrease in cardiovascular risk with reductions in LDL cholesterol."
McBride stressed, however, the importance of safety. Two exceptions to the LDL hypothesis are estrogen and torcetrapib; both reduced LDL-cholesterol levels, but the reductions were offset with other side effects, he said. Estrogen, for example, resulted in blood clotting and posed a cancer risk, while torcetrapib increased blood pressure. Ezetimibe, he said, is safe in that no known abnormalities have been noted with the drug.
Nissen is skeptical, however, noting that much of the cholesterol hypothesis is based on studies with statins. He is not sure, noting the absence of data and the lack of imaging support, that adding ezetimibe to simvastatin is the most effective means to reduce risk. Moving the patient to a high-dose, highly potent statin, such as atorvastatin (Lipitor, Pfizer) 80 mg, is supported by the evidence.
"There are many advocates out there who espouse lowering LDL cholesterol by any means possible," said Nissen. "But let's be clear: 95% of the studies that form the basis for the cholesterol hypothesis are based on studies of statins. I think, then, extrapolating from these statin trials to ezetimibe is a mistake."
Speaking with heartwire, most experts echoed the notion that it is still too early to determine whether using ezetimibe to lower LDL cholesterol is an effective means to reduce hard clinical events, such as MI. They point out that the ENHANCE study was small, enrolled difficult-to-treat FH patients, and was a surrogate-end-point study. Although the imaging end points were nonsignificant, it had been hoped that the ezetimibe and simvastatin combination, which reduced LDL cholesterol 58% compared with a 41% reduction with simvastatin alone, would lead to slower disease progression.
Dr Roger Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD) said that while it is certainly possible that not all the methods of reducing LDL cholesterol will be equally beneficial, he said that many statements made in the media have been alarmist.
"We are going to have a lot more data in the years to come, such as the completion of the IMPROVE-IT study, and it is only then that we're going to be able to know whether or not this particular method of lowering LDL is clinically beneficial."
The IMPROVE-IT study coming not so soon . . .
IMPROVE-IT is a multicenter, randomized, double-blind study that is enrolling 10 000 patients with ACS, including unstable angina, NSTEMI, and STEMI. Patients will be randomized to either ezetimibe 10 mg/simvastatin 40 mg or simvastatin 40 mg per day. Patients will be followed for over two years. The trial was not initiated until 2006, four years after the FDA approval of drug, and is not expected to be completed until 2011.
"I'll be blunt," Nissen told heartwire. "This was a case of the company putting all of their money into advertising instead of the needed clinical trials."
FH patients treated aggressively in the past
Commenting on the LDL hypothesis for heartwire, Dr Michael Blazing (Duke Clinical Research Institute, Durham, NC), who is involved in the IMPROVE-IT study, said that the ENHANCE study enrolled very-difficult-to-treat patients, those with FH and LDL-cholesterol levels exceeding 300 mg/dL. He stressed that the two-year change in mean carotid IMT between the treatment arms was neutral, and not doubled in the ezetimibe/simvastatin arm, as reported commonly in the media.
"In the meantime, some people are really going out on a limb," said Blazing. "At this point, we have data only from a surrogate-end-point trial and have no way of knowing what type of clinical effect the reductions in LDL will have. Moreover, we're extrapolating from a difficult patient population who has been treated aggressively in the past."
Dr Christie Ballantyne (Baylor College of Medicine, Houston, TX) told heartwire that too much has been made of an unpublished study. He agreed, however, that there are many questions that must be answered, such as what is the most effective way to lower LDL cholesterol after a high-dose statin failed to knock levels down low enough.
"I still think ezetimibe is a good option," said Ballantyne. "What I don't want people saying is that LDL is not important, although we know that it's not everything. This is a complex disease, but we want to avoid swinging too far, placing too much emphasis on an unpublished study, and dismissing 20 years of published research."
In his video blog, Topol also pointed to the new BusinessWeek article that questioned the value of statins, particularly the event protection conferred by atorvastatin. In the lengthy article, reporter John Carey crunches the numbers and shows that the number needed to treat to prevent one MI is 100, not a very impressive number. With reduction in strokes and longer-term follow-up, this benefit might increase, but the vast majority of patients are not really deriving protection from events, even though nearly all patients have a reduction of LDL cholesterol, said Topol.
"We've seen punching of holes in this whole LDL story, on multiple fronts," he said.
Berenson A. New questions on treating cholesterol. New York Times, January 17, 2008. Available at:
Carey J. Do cholesterol drugs do any good? BusinessWeek, January 17, 2008. Available at:
"Anti-Inflammatory" Diet May Improve Postprandial Glucose, Cardiovascular Health

Laurie Barclay, MD
January 23, 2008 — Dietary and lifestyle strategies for improving postprandial glucose, lipid profile, markers of inflammation, and cardiovascular health are reviewed in a state-of-the-art paper reported in the January 22 issue of the Journal of the American College of Cardiology.
"The highly processed, calorie-dense, nutrient-depleted diet favored in the current American culture frequently leads to exaggerated supraphysiological post-prandial spikes in blood glucose and lipids," write James H. O'Keefe, MD, from the Mid America Heart Institute and University of Missouri–Kansas City, and colleagues. "This state, called post-prandial dysmetabolism, induces immediate oxidant stress, which increases in direct proportion to the increases in glucose and triglycerides after a meal. The transient increase in free radicals acutely triggers atherogenic changes including inflammation, endothelial dysfunction, hypercoagulability, and sympathetic hyperactivity."
Even in individuals without diabetes, postprandial dysmetabolism independently predicts future cardiovascular events. Dietary improvements are associated with dramatic and immediate benefits in postprandial dysmetabolism.
To attenuate the increase in glucose, triglycerides, and inflammation after a meal, the review authors recommend a diet rich in minimally processed, high-fiber, plant-based foods, including vegetables and fruits, whole grains, legumes, and nuts. Other dietary interventions that can significantly ameliorate postprandial dysmetabolism include intake of lean protein, vinegar, fish oil, tea, and cinnamon. Additional benefits may result from calorie restriction, weight loss, exercise, and low-dose to moderate-dose alcohol.
Specific recommendations to improve postprandial glucose and triglycerides are as follows:
Select high-fiber carbohydrates with low glycemic index, including vegetables, fruits, whole grains, legumes, and nuts.
At all 3 meals, consume lean protein.
Eat approximately 1 handful of nuts daily (using a closed fist), consumed with vegetables, grains, berries, or other fruits.
Eat salad daily, consisting of leafy greens with dressing of vinegar and virgin olive oil.
Avoid highly processed foods and beverages, particularly those containing sugar, high-fructose corn syrup, white flour, or trans fats.
Limit portion sizes to modest quantities.
Maintain normal weight and avoid overweight or obesity. Waist circumference should be less than one half of height in inches.
Perform physical activity for at least 30 minutes or more daily, of at least moderate intensity.
For those with no history of substance abuse, consuming 1 alcoholic beverage before or with an evening meal may be considered.
"Experimental and epidemiological studies indicate that eating patterns, such as the traditional Mediterranean or Okinawan diets, that incorporate these types of foods and beverages reduce inflammation and cardiovascular risk," the review authors write. "This anti-inflammatory diet should be considered for the primary and secondary prevention of coronary artery disease and diabetes."
J Am Coll Cardiol. 2008;51:249-255.
Heart bypass best for multiple blockages

Bypass surgery remains the best option for heart patients with more than one clogged artery, according to the first big study to compare bypass with drug-coated stents. The new research dims hopes that the less drastic stent procedure would prove to be just as good for people with multiple blockages.
In the study, heart attack and death rates were lower among people who had surgery than those given artery-opening balloon angioplasty and stents — mesh cylinders oozing drugs to keep vessels from reclogging.
It is latest setback for drug-coated stents, which have revolutionized heart care and have been implanted in about 6 million people worldwide. They are far better at keeping vessels open than older bare metal stents. However, sales have been hurt in the past year by safety concerns and studies questioning the value of angioplasty itself for certain patients.
A second study gave stent makers some good news, finding that using these devices "off label," in non-approved situations, is not as dangerous as many had feared.
Both studies were published in Thursday's New England Journal of Medicine. Neither is definitive enough to resolve these issues, but they help guide doctors and patients confused about which treatment is best for whom.
The bypass study is "a sobering reality check" for people hoping that the newer drug-coated stents "would level the playing field" and make these treatments equally effective, Harvard University cardiologist Dr. Joseph Carrozza wrote in an accompanying editorial.
Blocked arteries cause chest pain by depriving the heart of needed blood, and can lead to a heart attack. One solution is bypass surgery, which reroutes blood vessels to detour around blockages. Angioplasty has emerged as a non-surgical alternative, in which a balloon is pushed into a blood vessel and inflated to flatten the clog, and stents are placed to keep the artery open.
Bypass has become less common as angioplasty has risen dramatically. In 2005, about 469,000 bypasses were performed on 261,000 patients. More than 1.2 million angioplasties were done, though many people had more than one procedure.
In 2005, Edward Hannan of the State University of New York at Albany published a study that found bypass to be better than angioplasty with bare metal stents for patients with multiple blockages. His new study makes a similar comparison, but with the newer drug-coated stents, which came out in 2003.
Researchers analyzed two state databases of 17,400 New York residents treated for multiple blockages in 2003 and 2004, and compared deaths and complications 18 months later.
Survival rates for both treatments were excellent, but bypass still showed a significant advantage after researchers took into account differences in how sick or old the patients were.
People with three clogged arteries had a survival rate of 94 percent after bypass compared with about 93 percent after stenting, which translated to a 20 percent lower risk of death. Those with two blockages had a survival rate of 96 percent after the operation compared with roughly 95 percent after stenting — about a 30 percent lower risk of death. The bypass group also needed fewer repeat procedures and suffered fewer heart attacks after treatment.
The New York State Department of Health helped pay for the study. The research covered the period in 2004 when former President Bill Clinton had quadruple bypass surgery, but it isn't known if his case was included, or if angioplasty was an option.
Stents still might be better for older patients and others who face greater risks from surgery, or for people who strongly prefer a less drastic treatment, Carrozza wrote. Some types of blockages also cannot be treated with stents.
Stent sales suffered last year after some studies suggested the drug-coated versions might lead to deadly blood clots months or years later. Danger was thought to be greater when stents were used "off label" for blockages other than types approved by the federal Food and Drug Administration.
The second study gave some reassurance that this may not be so risky. A team of U.S. and Canadian scientists looked at 6,551 patients who received either drug-coated stents or plain metal ones. Among those who received stents off-label, no difference in heart attacks or deaths was seen, though the bare-metal stent group needed more repeat procedures.
The findings "appear to validate off-label use" of drug-coated stents, but this single observational study is not enough to declare that safe, Carrozza wrote.
A Little Regular Exercise Extends Men's Lives

By Alan Mozes
WEDNESDAY, Jan. 23 (HealthDay News) -- Even a moderate amount of exercise can dramatically prolong a man's life, new research on middle-aged and elderly American veterans reveals.
The government-sponsored analysis -- the largest such study ever -- found that a regimen of brisk walking 30 minutes a day at least four to six days a week was enough to halve the risk of premature death from all causes.
"As you increase your ability to exercise -- increase your fitness -- you are decreasing in a step-wise fashion the risk of death," said study author Peter Kokkinos, director of the exercise testing and research lab in the cardiology department of the Veterans Affairs Medical Center in Washington, D.C.
That conclusion applies more or less equally to white and black men, regardless of their prior history of cardiovascular disease. According to Kokkinos, that may be because the veterans in the study all received the same level of care, regardless of income.
This evened the playing field, he said, giving him "great confidence" in the results, which will be published in the Feb. 5 issue of Circulation and were released online Jan. 22.
In the study, Kokkinos and his team reviewed information gathered by the VA from 15,660 black and white male patients treated either in Palo Alto, Calif., or in Washington, D.C.
The men ranged in age from 47 to 71 and had been referred to a VA medical facility for a clinically prescribed treadmill exercise test sometime between 1983 and 2006. All participants were asked to run until fatigued, at which point the researchers recorded the total amount of energy expended and oxygen consumed.
The numbers were then crunched into "metabolic equivalents," or METS. In turn, the researchers graded the fitness of each man according to his MET score, ranging from "low-fit" (below 5 METS) to "very-high fit" (above 10 METS).
By tracking fatalities through June 2007, Kokkinos and his colleagues found that for both black and white men it was their fitness level, rather than their age, blood pressure or body-mass index, that was most strongly linked to their future risk for death.
Every extra point in MET conferred a 14 percent reduction in the risk for death among black men, and a 12 percent reduction among whites. Among all participants, those categorized as "moderately fit" (5 to 7 METS) had about a 20 percent lower risk for death than "low-fit" men. "High-fit" men (7 to 10 METS) had a 50 percent lower risk, while the "very high fit" (10 METS or higher) cut their odds of an early death by 70 percent.
"The point is, it takes relatively little exercise to achieve the benefit we found," noted Kokkinos. "Approximately two to three hours per week of brisk walking per week. That's just 120 to 200 minutes per week. And this can be split up throughout the week, and throughout the day. So it's doable in the real world."
Alice H. Lichtenstein, director of the Cardiovascular Nutrition Lab at Tufts University's USDA Human Nutrition Research Center in Boston, agreed.
"What this finding demonstrates is that levels of physical activity that should be achievable by anyone can have a real benefit with respect to risk reduction," she said.
"What's really important to understand is that you don't need special clothes, special memberships, special equipment," added Lichtenstein, former chairwoman of the American Heart Association's nutrition committee. "It's something everyone can engage in. And although we don't know from this research that this applies to women as well, there's no reason to suspect that it wouldn't."

Wednesday, January 23, 2008

Bariatric Surgery Erases Type 2 Diabetes in Obese Patients

By John Gever
MELBOURNE, Australia, Jan. 22 -- Type 2 diabetes was virtually eliminated in three-quarters of obese patients two years after gastric banding surgery, researchers here said. Disease remission was seen in 22 of 30 patients (73%) who underwent the procedure, but in only four of 30 control patients (13%, P<0.001) receiving conventional diabetes treatment, reported John B. Dixon, M.B.B.S., Ph.D., of Monash University, and colleagues in the January 23 issue of the Journal of the American Medical Association. Remission was defined as fasting plasma glucose levels less than 126 mg/dL, glycated hemoglobin values less than 6.2%, and no use of oral hypoglycemic drugs or insulin.
This is the first randomized trial to study bariatric surgery as a treatment for type 2 diabetes in obese patients, the researchers said.
"This study presents strong evidence to support the early consideration of surgically induced loss of weight in the treatment of obese patients with type 2 diabetes," they concluded.
The researchers believe the antidiabetic effect follows from weight loss rather than by altering insulin resistance or beta-cell activity directly.
"Degree of weight loss, not the method, appears to be the major driver of glycemic improvement and diabetes remission in obese participants," they said.
In an interview, Dr. Dixon added, "The greater the weight loss, the more likely they were to remit."
After two years of follow-up, surgery patients weighed 19.6 kg less on average than those treated conventionally (95% CI: 15.2 to 23.8, P<0.001). Mean loss from baseline was 21.1 kg in the surgery patients and 1.5 kg in the control group.
Glycated hemoglobin values were 1.43 points lower in the surgery patients than in controls at the two-year evaluation (95% CI: 0.80 to 2.1, P<0.001). They decreased 1.81 points from baseline after surgery compared with a 0.38-point decrease with standard treatment.
Plasma insulin and glucose levels were also significantly decreased following surgery, with respect to both control therapy and baseline.
Other aspects of metabolic syndrome also improved more with surgery than conventional treatment. These included triglyceride levels and the ratio of high-density lipoprotein cholesterol to total cholesterol.
Entering the study, patients had body mass indices of 30 to 40 kg/m2 and had received a diagnosis of type 2 diabetes within the preceding two years. Evidence of renal impairment or diabetic retinopathy, history of substance addiction or mental illness, type 1 diabetes, diabetes secondary to another disease, recent major vascular event, portal hypertension, or internal malignancy were exclusion criteria.
Nearly all patients had hypertension and metabolic syndrome at enrollment. Mean age was about 47 and mean levels of glycated hemoglobin were 7.6% in the control group and 7.8% in those assigned to surgery.
The surgery involved laparoscopic placement of an adjustable gastric band by the pars flaccida technique.
Conventional treatment was better than ordinary, Dr. Dixon said. Patients were seen by a research team member every six weeks through the two-year study period. They received medications as individually determined by a diabetologist. Lifestyle modification programs focusing on diet and exercise were designed for each participant.
Adverse effects related to the surgery included one case of superficial wound infection at the access site, successfully treated with antibiotics. Two patients developed gastric pouch enlargement 10 months after placement. They underwent a second laparoscopic surgery to correct the problem. One patient was unable to tolerate the band and it was removed after two weeks.
An accompanying editorial by David E. Cummings, M.D., and David R. Flum, M.D., M.P.H., of the University of Washington in Seattle, highlighted the relatively mild degree of diabetes and its short duration in the patient sample.
"It is unclear whether secondary effects from weight loss alone after [gastric banding], without apparent direct antidiabetes surgical mechanisms, would suffice to reverse more severe, longstanding disease with greater beta-cell deterioration," they wrote.
Dr. Dixon agreed, but he added that the question should be tested in a future clinical trial.
Drs. Cummings and Flum also said that other studies have suggested much stronger antidiabetic effects for Roux-en-Y gastric bypass surgery. In those studies, diabetic remission has been observed within days or weeks of surgery, "long before substantial weight loss has occurred," they wrote.
That is true as well, Dr. Dixon said. But he emphasized the differences in risk between the two procedures. He said the literature suggests a mortality rate of about one in 200 for bypass surgery versus about one in 2,000 for the banding procedure. Bypass surgery also creates more problems with nutrient absorption, he said.
Nevertheless, Dr. Dixon said, bypass surgery could be considered for patients at the highest risk for diabetic complications.
"Surgery on the gastrointestinal tract and its effect on type 2 diabetes is a very exciting research area," he said.
The study was funded by Monash University through an unrestricted grant from Allergan Health.
Dr. Dixon reported financial relationships with the National Health and Medical Research Council, Allergan Health, and Novartis Australia. Other co-authors reported relationships with Eli Lilly, Novo Nordisc, sanofi-aventis, Alphapharm, and Abbott Australia.
Dr. Cummings and Dr. Flum reported receiving travel grants to attend a meeting sponsored by Johnson & Johnson, Autosuture, Allergan, Roche, Storz, GI Dynamics, Amylin, and Power Medical Interventions.
Primary source: JAMASource reference:Dixon J, et al "Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial" JAMA 2008; 299: 316-23. Additional source: JAMASource reference: Cummings D, Flum D, "Gastrointestinal surgery as a treatment for diabetes" JAMA 2008; 299: 341-43.
Dietary Guidelines May Have a Downside

By Judith Groch
NEW YORK, Jan. 22 -- With their weak standards of evidence, national dietary guidelines might actually do more harm than good, said researchers here.
Using guidelines against dietary fat promulgated in the late 1970s as a case in point, Paul R. Marantz, M.D., of Albert Einstein College of Medicine, and colleagues, noted that people may have been led to believe that limiting dietary fat gave them a green light to eat their fill of carbohydrates.
This association, they wrote online in the American Journal of Preventive Medicine, may have contributed to the current epidemic of obesity and overweight in the U.S.
National dietary guidelines have been promulgated based on scientific reasoning and indirect evidence, the researchers said.
In general, they said, weak evidentiary support has been accepted as adequate justification for the guidelines.
"This low standard of evidence is based on several misconceptions, most importantly the belief that such guidelines could not cause harm."
But, the researchers noted, in 2000, the Dietary Guideline Advisory Committee reversed the earlier 1995 recommendation to lower fat intake, saying that it might have been ill-advised and might actually have some potential for harm.
They quoted the 2000 committee statement that "an increasing prevalence of obesity in the United States has corresponded roughly with an absolute increase in carbohydrate consumption."
This increase may also have been influenced by marketing trends for low-fat foods, which although not entirely driven by the U.S. Dietary Guidelines, may have used an apparent governmental "seal of approval" for products such as fat-free cookies.
From 1971 through 2001, the researchers noted, absolute fat intake decreased by only 5% in men while fat as a percent of total calorie intake declined by 11%. In women, they said, "the difference was even starker: absolute fat intake actually increased by 11% while relative fat intake declined by 9%."
The temporal association between the recommendations and the increase in total calorie consumption does not prove causation, the researchers were careful to point out, but it raises the possibility of a net harmful effect of seemingly innocuous dietary advice, they said.
The researchers also pointed to advice on salt intake as another example of unintended consequences of a seemingly sensible recommendation, noting, however, that a blood pressure benefit may be trumped by harmful effects on plasma renin, insulin resistance, sympathetic nerve activity, and aldosterone levels.
A recent finding of no difference in total mortality between randomized sodium-intake groups has left the value of sodium reduction an open question, they said.
The trans fat issue, they said, provides another example. Although there is good evidence linking dietary trans fats to cardiovascular disease, though not with obesity, the net effect of the campaign against trans fats is that these fats will be replaced by "something else (unclear what)," they wrote.
Furthermore, as the vilification of dietary trans fats continues and marketing of other high-calorie foods with "0 grams trans fats" takes off, it should not be forgotten that trans fat consumption increased dramatically as margarine was promoted as the healthy alternative to butter.
To avoid possible unanticipated and adverse effects, specific and transparent classification of the quality of the evidence should attend guideline development and promulgation, the researchers said.
"When adequate evidence [for a guideline recommendation] is not available," they wrote, "the best option may be to issue no guideline."
In an accompanying comment, Steven Woolf, M.D., of Virginia Commonwealth University in Richmond, and Marion Nestle, Ph.D., of New York University, differed with the investigators, maintaining that the dietary guidelines are not the culprit in the obesity epidemic.
"The larger concerns," they said, "are poverty and an environment that promotes overeating and inactivity."
"Although we agree with many of the themes described by the authors of this study," Drs. Woolf and Nestle wrote, "we strongly disagree with their depiction of how the guidelines were developed, their characterization of the evidence on which the guidelines were based, and their indictment of public health guidance in general."
Nutrition research has had its share of "flip-flops" and is challenging perhaps more so than in other areas of public health or medicine, they wrote. For example, the time needed to measure health outcomes is so long that studies must often rely on surrogate measures, and every study is complicated by the enigma of whether foods or some combination or interactions of their nutrients are responsible for the outcomes.
It is true that messages about fat must be accompanied by messages about caloric balance and deal with other complex issues. But the solution is "not to abandon the enterprise but to reshape the message," they wrote.
A guideline cannot single-handedly change a nation's eating habits. Food preferences, portion sizes, and physical activity levels are products of advertising, the environment, and a milieu of other obesogenic influences, "not the consequence of a poorly distributed federal publication," they wrote.
"To scapegoat guidelines is to oversimplify the complex and to obfuscate the necessary -- albeit difficult -- task of confronting these larger determinants of obesity," Drs. Woolf and Nestle concluded.
No financial disclosures were reported by the authors of the paper or by the authors of the comment.
Primary source: American Journal of Preventive MedicineSource reference:Marantz P, et al "A call for higher standards of evidence for dietary guidelines" Am J Prev Med 2008: DOI: 1016/j.amepre.2007.11.017. Additional source: American Journal of Preventive MedicineSource reference: Woolf S, Nestle M, "Do dietary guidelines explain the obesity epidemic? Am J Prev Med 2008; DOI: 1016/j.amepre.2007.12.002.
Burgers, Fries, and Diet Soda Are Recipe for Metabolic Syndrome

By Peggy Peck
MINNEAPOLIS, Jan. 22 -- Middle-age adults who regularly eat a double burger, fries, and a diet soda for lunch or dinner increase their risk of incident metabolic syndrome by 25% compared with those who limit red meat to two servings a week. But eating healthy doesn't reduce the odds of developing metabolic syndrome, said Lyn M. Steffen, Ph.D., M.P.H., R.D., of the University of Minnesota, who studied the eating habits of more than 9,514 middle-age Americans. After nine years of follow-up, 3,782 of the participants in the Atherosclerosis Risk in Communities study had three or more of the risk factors that are used to define metabolic syndrome, Dr. Steffen and colleagues reported online in Circulation, Journal of the American Heart Association.
Unlike other studies that have investigated relationships between nutrients and cardiovascular risk, "we specifically studied food intake, since when we start to think about making recommendations it is easier to do so using the framework of real foods, eaten by real people," Dr. Steffen said.
The researchers assessed food intake using a 66-item food frequency questionnaire administered at three-year intervals. From the responses to those questions, they were able to categorize people into a Western-pattern diet or a prudent-pattern diet.
A Western diet contained high amounts of refined grains, processed meat, fried foods, red meat, eggs, and soda with little consumption of low-fat dairy products, fruits, and vegetables.
Prudent eating patterns, by contrast, favored cruciferous vegetables, carotinoid vegetables, fruit, fish and seafood, poultry, and whole grains, along with low-fat dairy products.
At baseline from 1987 through 1989, the study participants were between 45 and 64 years old, a population at risk for weight gain, which is associated with metabolic syndrome.
"After adjusting for demographic factors, smoking, physical activity, and energy intake, consumption of a Western dietary pattern (Ptrend≤0.03) was adversely associated with incident [metabolic syndrome]," the researchers found.
When they analyzed the results by specific foods, they found that meat (Ptrend <0.001), fried foods (Ptrend=0.02), and diet soda (Ptrend≤0.001) were all significantly associated with increased risk of metabolic syndrome, but consumption of dairy products -- especially yogurt and low-fat milk -- was beneficial (Ptrend=0.006).
Regular soda, which Dr. Steffen said was expected to increase risk of metabolic syndrome, was not associated with increased risk.
Dr. Steffen said the soda findings might reflect poorer glycemic control, which has been reported in other studies of diet sodas. Moreover, she said a study in rats suggested that the consumption of artificial sweeteners "impairs the body's ability to predict the caloric content of foods, and may lead to increased intake and body weight."
Dr. Steffen said the association between a Western-type diet and metabolic syndrome, although expected, was nonetheless striking for some individual foods.
"For example, we looked specifically at french fries and found that eating one serving a day increased the risk of developing incident metabolic syndrome by 10%," she said in an interview.
An unexpected finding was that consuming a prudent diet (i.e. one that had a high concentration of fruits, vegetables, whole grains) and low-fat dairy products did not reduce the risk of metabolic syndrome. "We had expected to see a benefit because we have seen a beneficial relationship in other studies," she said.
The researchers noted that their study was limited by its use of a questionnaire to calculate food intake, which may have allowed for reporting bias as well as misclassification of some foods. For example, the questionnaire was "not designed to differentiate whole grain from refined grain items in the food list," they wrote.
The study was funded by the National Heart, Lung, and Blood Institute.
Dr. Steffen and colleagues reported no financial disclosures.
Primary source: Circulation, Journal of the American Heart AssociationSource reference:Lutsey PL, et al "Dietary intake and the development of the metabolic syndrome: the ARIC study" Circulation 2008; DOI: 10.1161/CIRCULATIONAHA.107.716159.
Comorbidity Can Confound Prostate Cancer Treatment

By Charles Bankhead
BOSTON, Jan. 22 -- The best-laid plans of therapy for localized unfavorable-risk prostate cancer can be upset by pre-existing comorbidities, investigators here found. For instance, adding six months of androgen suppression to radiation improves overall survival by a significant 80%, Anthony V. D'Amico, M.D., Ph.D., of Harvard, and colleagues reported in the Jan. 23 issue of the Journal of the American Medical Association. But the reduction in mortality risk was seen only in men without significant comorbid conditions. In fact, men with moderate or severe comorbidity scores fared better with radiation alone, they added.
"The clinical significance of this finding is that pre-existing comorbid illness may increase the negative effects of specific anticancer treatments such as [androgen suppression therapy]," the authors concluded.
"Therefore, future randomized studies evaluating the impact on survival of adding novel therapies to the current standards of practice in men with clinically localized or locally advanced prostate cancer should consider a pre-randomization stratification by comorbidity score."
Several randomized studies have demonstrated prolongation of survival when androgen suppression is added to external-beam radiation for unfavorable localized and locally advanced disease.
However, pooled analyses of other randomized and cohort studies have indicated that androgen suppression therapy increases the risk of fatal and nonfatal cardiovascular events in older men, the authors said.
One possible explanation for the association between androgen suppression and increased cardiovascular risk is that the emergence of comorbid conditions with age may increase the negative effects of specific anticancer therapies, such as androgen suppression.
Dr. D'Amico and colleagues reported long-term follow-up data from a randomized study comparing six months of androgen suppression with radiation therapy versus radiation alone. They also analyzed survival data in subgroups defined by patients' level of comorbidity at baseline.
The study involved 206 men (median age 72.5) with localized or locally advanced prostate cancer and at least one unfavorable prognostic factor, defined as:
PSA level >10 ng/mL
Biopsy Gleason score of 7 to 10
Evidence of extracapsular extension
Evidence of seminal vesicle invasion
Additionally, each patient was assigned a baseline comorbidity score based on assessment by the Adult Comorbidity Evaluation 27. A patient's overall comorbidity was graded on a scale of 0 (none) to 3 (severe), determined by the severity of individual organ system decompensation and prognostic impact.
All patients were given three-dimensional conformal radiation therapy and were randomized to no additional therapy or to six months of androgen suppression. Initially, the primary endpoint was time to PSA recurrence. However, the protocol was modified before the first planned interim analysis to extend follow-up to allow evaluation of the prespecified secondary endpoints of overall and prostate cancer-specific survival.
After a median follow-up of 7.6 years, there were 44 deaths in the radiation-only group and 30 in the androgen suppression group. The difference translated into a significant survival benefit among men treated with androgen suppression in addition to radiation (hazard ratio: 1.8, P=0.01). Estimated eight-year survival was 74% with androgen suppression and 61% without.
Patients given androgen suppression therapy also had a significant reduction in prostate cancer-specific mortality. There were 14 prostate cancer deaths in the radiation-alone group versus four among patients given androgen suppression (HR: 4.1, P=0.01).
Analysis of the data by baseline comorbidity score showed that the survival benefit conferred by androgen suppression applied only to patients who had low comorbidity scores at baseline. Among patients with no or minimal baseline comorbidity scores (0 to 1), there were 31 deaths in the radiation-only group versus 11 in the androgen-suppression group (HR: 4.2, P<0.001).
In contrast, men with moderate or severe comorbidity had a lower all-cause mortality when treated with radiation alone (13 deaths versus 19, HR: 0.54, P=0.08).
"Our study suggested that the relevant underlying comorbidity may have been a prior history of MI more than six months before randomization, but numbers were too small to exclude other comorbidities, such as diabetes," the authors concluded.
"Health-related quality-of-life outcomes require further study," they continued. "Specifically, it is possible that while life expectancy may not be altered, health-related quality of life may be affected more in men with certain underlying comorbidities when [androgen suppression therapy] is administered."
The authors had no disclosures.
Primary source: JAMASource reference:D'Amico AV, et al "Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial" JAMA 2008; 299: 289-295.
Efficacy of Hypertension Drugs Modified by Gene Variants

By Michael Smith
BIRMINGHMAM, Ala., Jan. 22 -- The goal of a genetic scan to narrow the choice of a hypertension drug to the need of an individual patient, beyond trial and error, is a bit closer to reality.
In an analysis of more than 39,000 hypertension patients, gene variations appeared to play a role in which patients responded best to different hypertension drugs, found Donna Arnett, Ph.D., of the University of Alabama at Birmingham, and colleagues.
The finding "moves us one step closer toward the ultimate goal of providing individualized treatment guided by genetic information," Dr. Arnett and colleagues said in the Jan. 23 issue of the Journal of the American Medical Association.
But they cautioned that the research -- predicated on a post hoc substudy of a large randomized clinical trial -- is not yet ready for prime time.
Before the findings can be used by clinicians, Dr. Arnett and colleagues said, essential further research includes replicating the findings, exploring gene-gene and gene-environment interactions, and conducting cost-benefit analyses.
The research built on the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which randomized 42,418 hypertensive participants 55 or older from February 1994 through January 1998 and then followed them until March 2002.
Participants were randomized to a diuretic, a calcium antagonist, an angiotensin-converting enzyme inhibitor, or an alpha-blocker and the primary endpoint was fatal coronary heart disease or nonfatal myocardial infarction.
For the substudy -- dubbed Genetics of Hypertension Associated Treatment or GenHAT -- the researchers looked at a range of cardiovascular outcomes for the 39,114 participants with DNA available for study.
The GenHAT study became possible in 2003, when a test became available for single nucleotide polymorphisms (SNPs) in a gene called atrial natriuretic precursor A (NPPA), from which atrial natriuretic polypeptide (ANP) is derived.
Animal studies have shown that low levels of ANP, the diuretic that controls extracellular fluid volume and electrolyte homeostasis, lead to hypertension, while enhanced levels lead to hypotension.
Dr. Arnett and colleagues looked at two SNPs in NPPA that appeared likely to have functional consequences -- a guanine-adenine switch dubbed rs5063 and a thymine-cytosine switch dubbed rs5065.
The goal was to see whether having the different alleles of the gene had any effect on which of the four drugs was more efficacious.
In fact, analysis showed that rs5063 was not associated with any variations in effect, but the C alleles of the second SNP were associated with a better outcome if patients carrying them were randomized to the diuretic.
When comparing the diuretic and the calcium antagonist, for instance, lower event rates were found in univariate analyses for the C allele carriers than for the TT homozygous individuals.
Those with two copies of the C allele had a relative risk for coronary heart disease of 0.86, compared with 0.90 for those with one copy, and 1.09 for those with two T alleles. The differences were significant at P=0.03.
The corresponding relative risks for stroke were 1.18, 0.82, and 1.26, which was significant at P=0.01 when the two groups with a C allele were combined into one.
For all-cause mortality, having two C alleles led to a risk of 0.87, one copy to a risk of 0.98, and two T alleles to a risk of 1.12, which was significant at P=0.05.
In accord with the clinical findings, six-month changes in systolic blood pressure for those with the CC genotype were larger with the diuretic than with the other medications, while the majority (with the TT genotype) had a smaller range of variation. Results were similar for diastolic blood pressure.
After correction for multiple comparisons, none of the findings retained statistical significance, the researchers noted, but the consistency of associations remained in five of seven outcomes and "lends some credibility to the findings."
The study was supported by the National Heart, Lung, and Blood Institute and the NIH.
The researchers reported no financial conflicts.
Primary source: Journal of the American Medical Association Source reference:Lynch AI, et al "Pharmacogenetic association of the NPPA T2238C genetic variant with cardiovascular disease outcomes in patients with hypertension" JAMA 2008; 299: 296-307.
Dangerous MRSA Strain Evolved Recently from Common Ancestor

By Michael Smith
HAMILTON, Mont., Jan. 22 -- It may be no exaggeration to call the highly pathogenic community-acquired methicillin-resistant Staphylococcus aureus a superbug, researchers here found.
The recently identified USA300 strain, now widespread in the U.S., evolved from a single ancestor, according to Frank DeLeo, Ph.D., of the National Institute of Allergy and Infectious Diseases' Rocky Mountain Laboratories, and colleagues.
The USA300 strain of community-acquired MRSA, unknown until 2000, has become a leading cause of skin and soft-tissue disease in otherwise healthy people. But researchers had been puzzled about the origin of the USA300 strain.
Now, whole genomic sequencing shows that the USA300 isolates found across the country share a recent common ancestor, Dr. DeLeo and colleagues reported online in the Proceedings of the National Academy of Sciences.
The data rule out the competing hypothesis that various isolates derived from different ancestors had converged on the virulent USA300 strain, the researchers said.
The findings "add an evolutionary dimension to the epidemiology and emergence of USA300," Dr. DeLeo and colleagues said.
The mechanism appears to be similar to what happened in the 1950s, when a penicillin-resistant form of S. aureus (known as phage-type 80/81 S. aureus) caused a pandemic in U.S. hospitals and the community.
Currently, community-acquired MRSA is responsible for the majority of skin and soft-tissue infections in patients coming to U.S. emergency departments and the USA300 strain has been blamed for 67% of the invasive infections, the researchers noted.
Dr. DeLeo and colleagues used genetic mapping techniques to compare 10 USA300 isolates from around the U.S. with a reference strain that was sequenced in 2006.
They looked for single nucleotide polymorphisms (SNPs) -- single-letter changes in the DNA of the organism -- as well as other so-called regions of difference (RDs), such as insertions or deletions of genetic material.
The key finding was that eight of the 10 isolates were nearly identical, with an average difference from the reference strain of only 32 SNPs and from each other of just 50 SNPs, Dr. DeLeo and colleagues said.
An indication of relatively recent divergence is the ratio of non-synonymous to synonymous SNPs -- those that lead to a change in the derived polypeptide sequence versus those that make no change.
In this case, Dr. DeLeo and colleagues said, the ratio was a "relatively high" 1.9:1 and when only the eight most closely related isolates were considered, the ratio was 2.6:1.
The only reasonable interpretation "is that there has been very recent clonal expansion and geographic dissemination" of USA300, ruling out the possibility of convergent evolution, they said.
Interestingly, not all of the isolates were equally virulent in mice.
Animals infected with two of the isolates lived significantly longer (P=0.0002) than those infected with the reference strain -- even though all were genetically similar.
The inference is that even small changes in DNA can make large changes in the virulence of the organism, Dr. DeLeo and colleagues said.
"It is reasonable to conclude that within a short period there will be an increasing pool of derivative USA300 isolates that differ in virulence potential and/or pathogenicity," the researchers said.
The research was supported by NIAID.
The researchers reported no conflicts.
Primary source: Proceedings of the National Academy of SciencesSource reference:Kennedy AD, et al "Epidemic community-associated methicillin-resistant Staphylococcus aureus: recent clonal expansion and diversification" PNAS 2008; DOI: 10.1073/pnas.0710217105.
Poorer Kidney Function Associated With Cerebral Small Vessel Disease

Caroline Cassels
January 21, 2008 — New research suggests that poor kidney function, which is known to increase cardiovascular risk, might also be associated with subclinical markers of cerebral small vessel disease, independent of cardiovascular risk factors.
In a large population-based study, investigators from Erasmus Medical Center, the Netherlands, found that individuals with a lower glomerular filtration rate (GFR) had less deep white-matter volume (WMV), more white-matter lesions (WML), and a more frequent presence of lacunar infarcts, although this did not reach statistical significance.
Furthermore, adjustment for cardiovascular risk factors, such as blood pressure, C-reactive protein (CRP), and homocysteine, only marginally changed the association between GFR and cerebral small vessel disease, a common cause of stroke, cognitive decline, and dementia.
The study, led by M. Arfan Ikram, MD, was published in the January issue of Stroke.
The investigators speculate that, based on the study's findings, it is possible that GFR provides a better marker than concomitantly measured cardiovascular risk factors.
However, they add, more research to elucidate the exact mechanisms underlying the association of GFR with cerebral small vessel disease is required to confirm this hypothesis.
"Given that cerebral small vessel disease is related to an increased risk of stroke, cognitive decline, and dementia, our data provide important information in addition to the known risk of adverse cardiac outcomes in persons with poor kidney function. Thus, our study further emphasizes the importance of identifying those with subclinical kidney disease," they write.
Marginal Change After Risk-Factor Adjustment
Designed to examine age-related brain abnormalities on magnetic resonance imaging (MRI), the cross-sectional study, known as the Rotterdam Scan Study (RSS), is a substudy of the Rotterdam Study, a large population-based investigation of the prevalence, incidence, and determinants of chronic disease in the elderly.
The investigation looked at 484 subjects between the ages of 60 and 90 years who were free of dementia at the study outset and who underwent MRI scans and had their GFR measured using the Cockcroft-Gault equation.
Global, lobar, and deep volumes of gray and white matter and volume of WML were measured using automated MRI analysis. Lacunar infarcts were rated visually.
Blood glucose level, blood pressure, cholesterol, CRP, and homocysteine were measured in each participant. Subjects were also screened for a history of myocardial infarction and smoking.
The investigators found that subjects in the lowest quartile of kidney function had smaller brain volumes. However, they noted that this smaller brain volume was not attributable to smaller gray-matter volume but rather to smaller total and normal WMV.
They found no association between GFR and either lobar or deep gray-matter volume.
The authors report that, after adjustment for cardiovascular risk factors, the associations were marginally attenuated, but GFR was still related to volume of WML, to deep WMV, and to brain volume.
Collaboration Needed
In an accompanying editorial, Stephen L. Seliger, MD, MS, from the University of Maryland in Baltimore, and W.T. Longstreth Jr, MD, MPH, from the University of Washington in Seattle, note that the study adds to a growing body of evidence supporting a link between vascular disease of the kidney and the brain.
However, they add, at this point the underlying mechanisms are unclear.
"Understanding the interplay of vascular disease in these 2 organs holds the promise of finding novel means to reduce the risk of impaired function, especially in the brain. The path to this understanding begins with the type of study reported by Ikram and colleagues and requires the continued collaboration of nephrologists and neurologists," they write.
The study was supported by the Health Research and Development Council and the Netherlands Organization for Scientific Research.
Stroke. 2008; 39:55-61 Abstract, 5-6. Abstract
Cranberries May Help Prevent Urinary Tract Infections in Elderly Women

News Author: Laurie Barclay, MD
January 22, 2008 — Cranberries are effective in preventing urinary tract infections in elderly women, but evidence is less clear in the long-term for most populations, according to the results of a Cochrane systematic review published in the January 23 issue of the Cochrane Database of Systematic Reviews.
"Cranberries have been used widely for several decades for the prevention and treatment of urinary tract infections (UTIs)," write Ruth G. Jepson and J.C. Craig. "Cranberries contain a substance that can prevent bacteria from sticking on the walls of the bladder. This may help prevent bladder and other urinary tract infections."
The review authors searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Library), and the Internet through January 2007, and they also consulted companies involved in promoting and distributing cranberry products and checked reference lists of review articles and relevant studies.
Ten studies were identified meeting selection criteria of randomized controlled trials (RCTs) or quasi-RCTs that compared the efficacy of cranberry products with that of placebo, juice, or water for prevention of UTIs in all populations. The total number of participants enrolled was 1049.
Two authors independently reviewed and extracted data on methods, participants, interventions and outcomes, which were rates of symptomatic and asymptomatic UTIs, adverse effects, and treatment compliance. Whenever possible, relative risks (RR) were calculated, and when this was not feasible, data were summarized as a narrative synthesis. Cochrane criteria were used to grade the quality of the included trials and evidence.
Of the 10 included studies, 5 were crossover and 5 were parallel group; 7 compared cranberry/cranberry-lingonberry juice with placebo, juice, or water; and 4 studies compared cranberry tablets with placebo (1 study evaluated both juice and tablets).
Compared with placebo or control, cranberry products were associated with significantly reduced incidence of UTIs at 12 months (relative risk [RR], 0.65, 95% confidence interval [CI], 0.46 - 0.90). However, cranberry products were more effective in reducing the incidence of UTIs in women with recurrent UTIs vs elderly men and women or people who required urinary tract catheterization.
The evidence was inconclusive as to whether cranberry products are effective in older men and women, and current evidence suggests that they are ineffective in people with a neuropathic bladder.
The meta-analyses included only 4 studies, because the remaining 6 studies had methodologic issues or were missing data. Only 1 study reported a significant result regarding the outcome of symptomatic UTIs.
In all studies, adverse effects were frequent, and several studies had high rates of dropouts and withdrawals.
Remaining areas of uncertainty include optimal duration of use, dosage, and preparation (eg, juice, tablets, or capsules) of cranberry products.
"There is some evidence that cranberry juice may decrease the number of symptomatic UTIs over a 12 month period, particularly for women with recurrent UTIs," the reviewers write. "Its effectiveness for other groups is less certain. The large number of dropouts/withdrawals indicates that cranberry juice may not be acceptable over long periods of time."
The Nuffield Trust gave Ms. Jepson a short-term fellowship for this review. The review authors have disclosed no relevant financial relationships.
Cochrane Database Syst Rev. 2008;00:000-000.
Low Serum Concentration of Vitamin E Linked to Physical Decline in Older Persons

Laurie Barclay
January 22, 2008 — Low serum concentration of vitamin E, an indicator of poor nutrition, is associated with subsequent physical decline among community-dwelling older adults, according to the results of a study reported in the January 23 issue of the Journal of the American Medical Association.
"Maintaining independence of older persons is a public health priority, and identifying the factors that contribute to decline in physical function is needed to prevent or postpone the disablement process," write Benedetta Bartali, RD, PhD, from Cornell University in Ithaca, New York, and colleagues. "The potential deleterious effect of poor nutrition on decline in physical function in older persons isunclear. . . . The purpose of this study was to determine whether a low concentration of specific micronutrients is associated with subsequent decline in physical function."
The investigators analyzed data from a longitudinal study of 698 community-dwelling persons 65 years or older who were randomly selected from a population registry in Tuscany, Italy. Baseline evaluation was performed from November 1, 1998, through May 28, 2000, and the 3-year follow-up evaluations from November 1, 2001, through March 30, 2003.
Decline in physical function during the 3-year follow-up was defined as a loss of 1 or more points in the Short Physical Performance Battery score. With the top 3 quartiles of each nutrient combined as the reference group, odds ratios were calculated for the lowest quartile. To confirm the validity of these results, the study authors used 2 additional and complementary analytical approaches.
Mean decrease in the Short Physical Performance Battery score was 1.1 point. Only a low concentration of vitamin E (< 1.1 μg/mL [< 24.9 μmol/L]) was significantly associated with subsequent decline in physical function, based on a logistic regression analysis with adjustment for potential confounders. Odds ratio for the association of lowest alpha-tocopherol quartile with at least a 1-point decline in physical function was 1.62 (95% confidence interval, 1.11 - 2.36;P = .01).
Baseline concentration of vitamin E was significantly associated with the Short Physical Performance Battery score at follow-up, in a general linear model with vitamin E analyzed as a continuous measure, after adjustment for potential confounders and baseline Short Physical Performance Battery score (β =.023; P = .01).
The strongest predictors of decline in physical function were age older than 81 years and vitamin E (in participants aged 70 - 80 years), based on classification and regression tree analysis. Physical decline occurred in 84% and 60%, respectively (misclassification error rate, 0.33).
"These results provide empirical evidence that a low serum concentration of vitamin E is associated with subsequent decline in physical function among community-living older adults," the study authors write.
Limitations of the study include bias by loss to follow-up, use of an Italian population–based sample limiting generalizability, vitamin D associated with decline in physical function in bivariate analysis but not in adjusted analyses, possible false-positive results because 6 micronutrient levels were tested, and possibly inadequate adjustments for multiple potential confounders.
"Although the findings from this epidemiological study cannot establish causality, they provide a solid base that low concentration of vitamin E contributes to decline in physical function," the study authors conclude. "Clinical trials may be warranted to determine whether optimal concentration of vitamin E reduces functional decline and the onset of disability in older persons with a low concentration of vitamin E."
The Invecchiare in Chianti study was supported by the Italian Ministry of Health and in part by the National Institute on Aging, National Institutes of Health. Funding for vitamin E assessment was provided by Bracco Imaging SpA, Italy. Some of the study authors have disclosed various financial relationships with the National Institute on Aging, the Yale Claude D. Pepper Older Americans Independence Center, and Yale University School of Medicine. The remaining study authors have disclosed no relevant financial relationships.
JAMA. 2008;299:308-315.

Tuesday, January 22, 2008

What That Cholesterol Trial Didn’t Show

The cholesterol drug Vytorin became known for its commercials showing people who look oddly similar to foods like tacos and banana cream pie. But now Vytorin is getting attention that is anything but funny.
The medicine combines Zocor, a cholesterol-lowering statin, with Zetia, a drug that limits cholesterol’s absorption into the body, and the hope was that the combination would make it more effective than either drug standing alone. But last week Vytorin’s makers, Merck and Schering-Plough, announced that in a small study it had done no better than Zocor alone in slowing the growth of arterial plaque, which can lead to heart attacks. There’s nothing particularly alarming about the findings (unless you’re a shareholder, perhaps).
But the news set off a panic among patients using cholesterol drugs. One doctor said he assigned a nurse full time to take the calls “and convince patients not to stop their medicine.” Another patient argued with his doctor, claiming the study showed that the drug doubled heart attack risk. (It didn’t; the study wasn’t designed to measure heart attacks.)
“I think this study is being interpreted wrong,” said Dr. Paul D. Thompson, director of cardiology at Hartford Hospital, who personally uses Zetia and (like most of the doctors quoted in this article) has consulted with makers of cholesterol drugs.
He pointed out that Vytorin users did experience a larger drop in cholesterol than the Zocor users. The disappointment was that the decline didn’t translate into a bigger benefit in arterial health. “It didn’t show harm,” Dr. Thompson said. “There were no more cardiac events, no more side effects. There was just no change.”
The fallout from the study was not limited to Vytorin. It has led to a whole new set of questions for scientists about cholesterol drugs. Is lowering LDL, the “bad” cholesterol, all that counts? Or must a drug also raise HDL, the “good” cholesterol, and fight inflammation?
Adding to the confusion, the Vytorin makers dragged their feet on releasing the results, issued the findings in a press release rather than a medical journal and made a lot of people mad.
“Failed trials are important,” said Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic. “The reason the medical community is upset about the delay in reporting this is that we learn as much from a study that fails as we do from a study that succeeds. People are not happy that we didn’t learn about this sooner.”
Dr. Nissen, who says he donates his drug-consulting fees to charity and doesn’t take a tax deduction, added that the study raised interesting scientific questions about the differences in cholesterol drugs.
The most popular — the statins, including Lipitor and Zocor — reduce the amount of cholesterol produced by the liver. In some studies, statins have lowered heart attack risk by 30 percent or more in high-risk patients. Statins also raise HDL levels and have an anti-inflammatory effect. The problem is that statins, particularly at high doses, can have a number of side effects, including muscle pain.
Zetia has a smaller anti-LDL effect than statins, and little effect on HDL or inflammation. On the plus side, because it works primarily in the digestive tract, it potentially has fewer side effects.
Vytorin, by combining Zocor and Zetia, produces a bigger drop in cholesterol than either drug could do alone, and without a marked increase in side effects. The problem is that there are no long-term studies showing that using the drug translates into fewer heart attacks or strokes.
The latest study was a step in that direction. It didn’t set out to measure heart attacks or strokes, but it did look at whether Vytorin slowed plaque buildup on artery walls more than a statin alone.
It didn’t. While it’s been reported that the Vytorin users had more plaque than the Zocor users, that’s not a scientifically correct reading of the data: the difference between the two groups was not statistically significant.
Most important, perhaps, nothing about the trial undermines the settled wisdom about cholesterol and heart disease. The science still shows that lower cholesterol is better, however you achieve it.
“Every way in which we have lowered LDL in the past” has been shown to reduce heart attacks and strokes, said Peter Libby, chief of cardiovascular medicine at Brigham and Women’s Hospital in Boston, who has consulted with drug companies. “All of these different routes to lowering bad cholesterol are correlated with a clinical benefit.”
To be sure, not everyone agrees that drugs are the best way to achieve lower cholesterol. But the Vytorin disappointment doesn’t “mean the whole concept is wrong,” said Dr. Daniel J. Rader, director of the preventive cardiology and lipid clinic at the University of Pennsylvania School of Medicine, who has also consulted with drug companies. “I firmly believe lowering cholesterol is the most validated, most important way we can reduce our risk of heart disease and stroke. Get your LDL down, and the lower the better.”
In fact, the real lesson of the Vytorin confusion may be exactly what its makers have promoted.
“It actually does get back to what the Vytorin commercials show,” said Dr. Nieca Goldberg, medical director of the women’s heart program at New York University, who does not consult for cholesterol drug companies. “Cholesterol comes from what you eat and your family history. I always put in a plug for modifying your diet and exercise. It may not bring about as big of a reduction as medication does, but it helps.”
FDA Okays Adjuvant Trastuzumab (Herceptin) as Monotherapy

By Peggy Peck
SOUTH SAN FRANCISCO, Jan. 21 -- The FDA has given trastuzumab (Herceptin) the additional indication of adjuvant monotherapy for early-stage HER2-positive breast cancer, Genentech announced here.
The company said the FDA decision was predicated on one-year data from the HERA (HERceptin Adjuvant) trial. It found a significant 46% reduction in recurrence among women who took trastuzumab for 52 weeks following multimodality anthracycline-based therapy compared with controls.
The HERA trial also reported a significant increase in disease-free survival among women who received adjuvant therapy with trastuzumab.
Trastuzumab was, however, associated with a higher rate of congestive heart failure -- 2% versus 0.3% in the control group.
Serious infusion reactions -- including fatal infusion reactions -- and pulmonary toxicity have also been reported with trastuzumab. In most cases symptoms occurred during infusion or within 24 hours of infusion.
Trastuzumab infusion should be interrupted for patients with dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Trastuzumab should be discontinued for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.
High-Quality Preop Ultrasound Improves Evaluation of Adnexal Masses

By Charles Bankhead
LONDON, Jan. 21 -- For suspected ovarian cancer, high-quality ultrasonography can double the sensitivity of accurate diagnoses, help reduce major staging procedures, and shorten hospital stays, investigators here concluded.
Action Points --->
Explain to interested patients that physicians' ability to evaluate adnexal masses, including ovarian cancer, improves significantly with involvement of an experienced ultrasonographer.
Specialists in gynecologic ultrasound provided a likely histologic diagnosis in 99% of 150 cases compared with 52% for less experienced ultrasonographers, Joseph Yazbek, M.D., of Guy's and St. Thomas' Hospital, and colleagues reported in the February issue of the Lancet Oncology.
Better imaging studies led to 40% fewer major staging procedures. High-quality ultrasonography had a sensitivity for cancer diagnosis that was double that of less experienced ultrasonographers.
"The effect of expert scanning might be even greater if used in the primary assessment of ovarian pathology," the authors said. "Increased confidence in the diagnosis of benign ovarian lesions is likely to decrease the need for additional diagnostic tests ... and also decrease the number of referrals to regional cancer centers."
Ultrasonography reliably detects adnexal abnormalities and is used routinely in the assessment of patients with gynecologic complaints. However, the imaging modality's ability to establish the nature of an adnexal tumor varies and depends primarily on the experience and skill of the operator, the authors said.
Routine (level II) ultrasonography is usually performed by less experienced operators, probably leading to lower overall accuracy, the authors continued. Theoretically, higher-quality ultrasonography could have a major impact on the evaluation of adnexal masses because of the different approaches to management of ovarian cancer versus benign tumors.
Dr. Yazbek and colleagues sought to determine whether level III (experienced) ultrasonography has a measurable impact on management of adnexal masses compared with level II ultrasonography. They randomized 150 patients with suspected ovarian cancer to evaluation by level II or level III ultrasonographers. The primary endpoint was the number of major surgical staging procedures in each study group.
The results showed that 27 of 73 (37%) patients in the level II group underwent major surgical staging procedures (including laparotomy and at least an oophorectomy and omental biopsy) versus 17 of 77 (22%) in the level III group (P=0.049). The total number of surgical procedures was similar in the two groups (35 of 73 versus 33 of 77).
Among patients who had surgical procedures, the median hospital stay was six days in the level II group and five days in the level III group (P=0.01).
Level III ultrasonography provided a likely histologic diagnosis to physicians in 76 of 77 cases compared with 38 of 73 with level II ultrasonography. Eighteen of the 150 patients had final diagnoses of ovarian malignancy. Level II ultrasonography had a sensitivity of 40% and specificity of 100%, compared with 88% sensitivity and 96% specificity for level III ultrasonography.
The authors declared no conflicts of interest.
Primary source: The Lancet OncologySource reference:Yazbek J, et al "Effect of quality of gynecological ultrasonography on management of patients with suspected ovarian cancer: a randomized controlled trial" Lancet Oncol 2008; DOI: 10.1016/S1470-2045(08)70005-6.
'Ugly Duckling' Moles May Be Melanomas

By Judith Groch
NEW YORK, Jan. 21 -- An irregularly pigmented mole that looks different from other irregularly pigmented moles in the same person -- an "ugly duckling" -- is likely to be a malignant melanoma, according to a preliminary study. In a small study, all five melanomas and only three of 140 benign lesions (2.1%) were identified as ugly ducklings by two-thirds of hospital-staff participants with varying expertise, reported Ashfaq Marghoob, M.D., of Memorial Sloan-Kettering Cancer Center here, and colleagues in the January issue of the Archives of Dermatology.
Nevi are among the most important known risk factors for malignant melanoma in adults, and the skin cancer is more common in individuals with many nevi, including dysplastic ones, Dr. Marghoob's team wrote.
The challenge for clinicians who diagnose and treat pigmented skin lesions is to distinguish between melanoma and similar-looking benign lesions. There is an overlap in the moles' clinical features that leads to missed melanomas and excessive excision of benign lesions, the researchers said.
In 1998, investigators introduced the ugly duckling concept to demonstrate that nevi in the same individual tend to resemble one another and that those that deviate from the pattern tend to be melanomas.
To determine whether the ugly duckling sign is sensitive for melanoma detection, the researchers had 34 staff members of a dermatology clinic examine baseline back images of 12 patients.
The images, supplemented with close-up clinical images, were obtained from a database of standardized patient images. All 12 patients had at least eight atypical moles on the back, and in five patients, one of the lesions was a histologically confirmed melanoma.
The 34 observers included eight pigmented-lesion specialists, 13 general dermatologists, five dermatology nurses, and eight members of the nonclinical staff.
Participants were asked to evaluate whether the images showed any lesions on the back that differed from other nevi.
A lesion was considered a generally apparent ugly duckling if it was perceived as different by at least two-thirds of the participants.
Sensitivity was defined as the fraction of melanomas identified as different. Specificity was defined as the number of nevi not identified as different divided by the total number evaluated.
All five melanomas (100%) and only three of 140 benign lesions (two nevi and one seborrheic keratosis) were generally apparent as different, meaning that they were ugly ducklings.
The agreement on ugly ducklings decreased among participants in the groups with less expertise. The sensitivity of the ugly duckling sign for melanoma detection was 90% for the whole group, 100% for specialized dermatologists, 89% for general dermatologists, 88% for nurses, and 85% for nonclinicians.
The melanomas were apparent as being different to at least 85% of participants, whereas the agreement rate on the benign lesions perceived as being different was 76% at most, the researchers said.
Four lesions were generally apparent as completely different, all being melanomas. The single melanoma that was not generally apparent as completely different was an irregular brown macule, one centimeter in diameter, with a central black area. Nevertheless, the pigmented-lesion specialists made a correct identification.
Still, the values for all parameters were good in all subgroups of participants, the researchers said. Identification of ugly ducklings showed good sensitivity (0.87) and specificity (0.83) and diagnostic accuracy (0.87) for the detection of melanoma, even among nonclinicians.
Interestingly, the researchers noted, pigmented seborrheic keratosis and melanoma can resemble each other, and the seborrheic keratoses are unlikely to appear similar to a patient's prevalent nevus pattern. Thus, these lesions may be the Achilles' heel of the ugly duckling strategy, they said.
A limitation of the study, the investigators noted, is that assessment was done in a virtual setting rather than a real-time examination.
Also, dermoscopy was not used, possibly affecting diagnosis for those who use the method frequently in clinical practice.
Furthermore, they said, sensitivity and specificity values were primarily used as a means of measuring quantitative differences among expertise levels, and these values may not reflect actual values in the real world.
Finally, they said, the term "different" -- size, color, shape, or a combination -- was not defined precisely.
These preliminary findings, the researchers wrote, should be further assessed to allow refinement of the ugly duckling sign. However, they said, the sign may prove a useful screening strategy for primary health care providers and even for self-examination.
No financial conflicts were reported.
Primary source: Archives of DermatologySource reference:Scope A, et al "The 'ugly duckling' sign: agreement between observers" Arch Dermatol 2008; 144: 58-64.