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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
July 16, 2011

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Even Short-Term NSAID Use Associated with Cardiovascular Events
Evaluation, Treatment, and Prevention of Vitamin D Deficiency in Infants and Children
Evaluation, Treatment, and Prevention of Vitamin D Deficiency
Pass on HbA1c for Detecting Diabetes in Adolescents
Surgery Doesn't Trump Rehabilitation in Patients with Degenerative Disk Disease
A Supplement That Works for Alzheimer Disease?
Transdermal Estrogen Might Not Raise Risk for Recurrent Thrombosis
Diet Drinks Added Fat, Aspartame Made Mice Diabetic
Predicting Fracture Risk in Patients with Type 2 Diabetes
Smoking During Pregnancy Linked to Increased Risk for Birth Defects
Don't Miss the New AHA Recommendations on Triglycerides
Triglycerides and Cardiovascular Disease: The Experts Speak
AN ADDITIONAL PERSPECTIVE FROM the Journal Watch general medicine EDITOR-in-chief:
Cumulative Antibiotic Exposure Is Associated with Risk for C. difficile Infection
Newer Prostate Cancer Drugs Add Months to Life — at High Cost
Smoking Increases the Risk for Prostate Cancer Recurrence and Mortality
Intensified Early Treatment of Subclinical Diabetes: No Benefit at 5 Years
Painless Diabetic Motor Neuropathy
Breast-Conserving Therapy vs. Mastectomy for Triple-Negative Breast Cancer
Ovarian Cancer Screening: No Advantage
Viewing TV, Computers or Video Games Before Bedtime and Watching Violent
  Content Affect Kids' Sleep
Thyroid Autoantibodies and Excess Risk for Miscarriage and Preterm Birth
BMI and Efficacy of Endocrine Therapy for Premenopausal Breast Cancer

Circulation 2011 May 24; 123:2226
Even Short-Term NSAID Use Associated with Cardiovascular Events
Registry data show adverse effects of both selective cyclooxygenase-2 inhibitors and nonselective agents within the first week of treatment.
     Since 2007, practice guidelines have advised clinicians about the risks of nonsteroidal anti-inflammatory drug (NSAID) use in patients with known cardiovascular disease or at high risk for ischemic heart disease. However, whether short-term NSAID use (e.g., for less than a week) can worsen outcomes in such patients is unclear. Therefore, investigators used data from the Danish National Patient Registry to assess the impact of NSAID use in >83,000 patients (mean age, 68; 63% men) after hospitalization for first myocardial infarction (MI) from 1997 through 2006.
     More than 42% of the cohort received prescriptions for NSAIDs including ibuprofen (23%), diclofenac (13%), rofecoxib (5%), celecoxib (5%), and naproxen (2%). During follow-up, the primary outcome, a composite of death and recurrent MI, occurred in 42.1% of NSAID recipients. Compared with the overall study population, risk for a primary endpoint in NSAID recipients was significantly elevated in the first week of NSAID treatment (hazard ratio, 1.45), and the increase in risk remained significant throughout treatment (>90 days; HR, 1.55). In individual analysis, all NSAIDs except naproxen were associated with an increased risk for the primary outcome. Diclofenac conferred the highest risk, with a hazard ratio (3.26 in the first week of treatment) higher than that of rofecoxib, which was withdrawn from the U.S. market in 2004.
     Comment: In this large, national study, NSAIDs — many of which are available without a prescription — were associated with a 45% increase in risk for recurrent MI or death within the first week of treatment in post-MI patients. When NSAID treatment was continued for 3 months, the increase in risk rose to 55%. It appears that no NSAID, no matter how short the duration of use, is without possible cardiovascular side effects in patients with coronary artery disease.
JoAnne M. Foody, MD Published in Journal Watch Cardiology June 8, 2011
     Citation(s): Schjerning Olsen A-M et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: A nationwide cohort study. Circulation 2011 May 24; 123:2226.
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MM: Nothing has really changed here. We still are in the dark and don’t know what is happening with our kids. Kids need outdoor play and D3 supplementation. That is the best combination approach. If a child is nursing, then the mom needs sun exposure and D3 supplementation for the baby.
J Clin Endocrinol Metab 2011 Jun 6
Evaluation, Treatment, and Prevention of Vitamin D Deficiency in Infants
and Children

Risk factors in children include breast-feeding without vitamin D supplementation, dark skin pigmentation, and maternal vitamin D deficiency.
     The Endocrine Society has published a new practice guideline on vitamin D deficiency. This summary covers key points of the guideline relevant to children (the adult portion can be found at JW Gen Med Jun 23 2011).

     Comment: Despite the plethora of recent publications on vitamin D and the apparent association between vitamin D deficiency and many diseases, the only fundamental change in vitamin D recommendations in the pediatric population has been an increase in the requirement from 400 IU to 600 IU in children older than 1 year. Population-wide screening for vitamin D deficiency is not recommended.
Howard Bauchner, MD Published in Journal Watch General Medicine June 23, 2011
     Citation(s): Holick MF et al. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011 Jun 6; [e-pub ahead of print]. (http://dx.doi.org/10.1210/jc.2011-0385)
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MM: I’ve been a great proponent of use of vitamin D3 as well as testing to see what your levels are. That has not changed. What has changed is my opinion of the frequency. Test annually along with your annual check-up. More often than that is not warranted. Annual testing should be sufficient.
J Clin Endocrinol Metab 2011 Jun 6
Evaluation, Treatment, and Prevention of Vitamin D Deficiency
A new practice guideline recommends against routinely measuring serum vitamin D levels
in adults.

     The Endocrine Society has published a new practice guideline on vitamin D deficiency. This summary covers portions of the guideline that are relevant to adult medicine (the pediatric portion is covered elsewhere; JW Gen Med Jun 23 2011). Key points follow:

     Comment: Because many clinicians routinely check vitamin D levels these days, the guideline's rejection of population-wide screening is perhaps the key point for clinicians. Unfortunately, for average-risk adults, the guideline doesn't explicitly say whether clinicians should recommend daily supplements (600–800 IU) universally or should evaluate, case-by-case, whether a given person's sun exposure and dietary intake likely ensure sufficient vitamin D.
Allan S. Brett, MD Published in Journal Watch General Medicine June 23, 2011
     Citation(s):Holick MF et al. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011 Jun 6; [e-pub ahead of print]. (http://dx.doi.org/10.1210/jc.2011-0385)
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J Pediatr 2011 Jun; 158:947.e3
Pass on HbA1c for Detecting Diabetes in Adolescents
HbA1c did not perform as well as traditional measures for diagnosing diabetes mellitus in high-risk adolescents.
     In 2009, an international committee of diabetes experts recommended that glycosylated hemoglobin (HbA1c) replace fasting plasma glucose (FPG) and 2-hour plasma glucose levels for diagnosing diabetes mellitus in adolescents and adults. The committee and the American Diabetes Association (ADA) also recommend HbA1c testing for screening asymptomatic overweight and obese adolescents. However, the recommended HbA1c cutoffs were derived from data from adults. Therefore, investigators examined the accuracy of the recommended HbA1c cutoff value of ≥6.5% for diagnosis of diabetes in 1156 asymptomatic overweight and obese adolescents (age range, 12–18 years) who participated in the National Health and Nutritional Examination Surveys (NHANES 1999–2006).
     Compared with an FPG cutoff value ≥126 mg/dL, the HbA1c cutoff of 6.5% had a sensitivity of 75.0% and a specificity of 99.9% for detecting diabetes mellitus in adolescents. However, only four adolescents had undiagnosed diabetes mellitus; this low prevalence resulted in a wide 95% confidence interval. Compared with an FPG cutoff value ≥100 and <125 mg/dL for detecting prediabetes, the sensitivity of the HbA1c cutoff value of 6.0% (and the ADA cutoff value of 5.7%) was very low (<5%).
     Comment: Although use of glycosylated hemoglobin is appealing because the test does not require patients to be fasting, this study argues against using HbA1c for diagnosis of diabetes mellitus or prediabetes in adolescents. The authors acknowledge that their results were limited by the small number of adolescents with undiagnosed diabetes mellitus and the absence of repeat testing. Until we have more-definitive studies to guide us, I would stick with measuring fasting plasma glucose or 2-hour plasma glucose in adolescents.
Alain Joffe, MD, MPH, FAAP Published in Journal Watch Pediatrics and Adolescent Medicine July 13, 2011
     Citation(s): Lee JM et al. Diagnosis of diabetes using hemoglobin A1c: Should recommendations in adults be extrapolated to adolescents? J Pediatr 2011 Jun; 158:947.e3.
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BMJ 2011 May 19; 342:d2786
Surgery Doesn't Trump Rehabilitation in Patients with Degenerative Disk Disease
Disk prosthesis surgery and nonsurgical rehabilitation led to clinically similar results.
     Two surgical procedures are performed commonly in patients afflicted with chronic low back pain and degenerated disks: spinal fusion surgery and prosthetic disk replacement surgery. However, in a previous trial, spinal fusion surgery was not better than disk replacement or nonsurgical rehabilitation (JW Gen Med Jul 1 2005); whether disk replacement is superior to rehabilitation is unknown. In a multicenter randomized controlled trial, investigators in Norway compared disk replacement surgery with nonsurgical multidisciplinary treatment (i.e., cognitive and rehabilitation therapy that involved physiatrists, therapists, nurses, and social workers). The 173 enrolled patients (age range, 25–55) suffered from low back pain for ≥1 year, had undergone physical therapy or chiropractic care for ≥6 months, and exhibited degenerative intervertebral disk changes at L4/L5, L5/S1, or both. Patients with nerve root compression from herniated disks were excluded.
     At 2 years, a small significant difference in mean scores on the Oswestry disability index favored surgery; however, the difference did not reach a prespecified threshold for clinical importance. Several secondary outcomes favored surgery, but no differences were noted between groups in return to work, life satisfaction, fear avoidance beliefs, drug use, or scores on a back performance scale.
     Comment: Surgery with disk prosthesis was not clearly superior to nonsurgical multidisciplinary treatment in patients with chronic low back pain attributed to degenerative disk disease. As an editorialist stated, the nonsurgical approach "is cheaper, safer, and less disruptive to people's lifestyle than surgery, and it gives a long term benefit." However, note that these results do not apply to people with nerve root compression from herniated disks or spinal stenosis.
Paul S. Mueller, MD, MPH, FACP Published in Journal Watch General Medicine July 12, 2011
     Citation(s):Hellum C et al. Surgery with disc prosthesis versus rehabilitation in patients with low back pain and degenerative disc: Two year follow-up of randomised study. BMJ 2011 May 19; 342:d2786. (http://dx.doi.org/10.1136/bmj.d2786)
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Neurology 2011 Apr 19; 76:1389
A Supplement That Works for Alzheimer Disease?
Huperzine A may improve cognition.
     Huperzine A is a natural acetylcholinesterase (AChE) inhibitor derived from Huperzia serrata (an herb used in Chinese medicine) and available in health food stores. In this multicenter, randomized, placebo-controlled, double-blind, partly industry-supported, phase II study, researchers studied the effects of two dosages of huperzine A in 210 patients age 50 or older with probable Alzheimer disease (AD).
     Participants had mild-to-moderate dementia (Mini-Mental State Examination [MMSE] scores, 10–24); mean age was 78 (64% women). The three treatment groups were huperzine A 200 µg twice daily (after 2 weeks' titration at 100 µg twice daily), huperzine A 400 µg twice daily (after titration at lower doses for 6 weeks), and placebo. The study lasted for 24 weeks, but 16-week results are reported here; the primary outcome was change on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) with the 200-µg dose.
     No significant improvement was seen with the 200-µg dose on ADAS-Cog or MMSE. However, in a secondary analysis, improvement with 400 µg compared with placebo was seen on ADAS-Cog at weeks 11 and 16 and on MMSE scores at week 16. Most participants who had previously discontinued other AChE inhibitors because of side effects were able to tolerate huperzine A. Of the huperzine A recipients, 8% discontinued treatment because of adverse events (typically, nausea).
     Comment: Although we are generally skeptical about supplements and have concerns about manufacturing standards, some supplements have therapeutic efficacy (and independent testing centers exist — e.g., http://www.consumerlab.com). Still, the therapeutic dose of supplements often remains unknown. In this study, the predicted optimal dose was ineffective, but a secondary analysis suggested efficacy for a higher dose. Huperzine A may be an option for patients who require treatment with AChE inhibitors. A prospective study with the higher dose is needed to confirm these results.
Jonathan Silver, MD Published in Journal Watch Psychiatry May 23, 2011
     Citation(s):Rafii MS et al for the Alzheimer's Disease Cooperative Study. A phase II trial of huperzine A in mild to moderate Alzheimer disease. Neurology 2011 Apr 19; 76:1389.
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Menopause 2011 May; 18:488.
Transdermal Estrogen Might Not Raise Risk for Recurrent Thrombosis
In a small study, oral — but not transdermal — estrogen was associated with excess risk for recurrent venous thromboembolism.
     Oral estrogen therapy raises risk for venous thromboembolism (VTE) in postmenopausal women, so its use generally is contraindicated in women with histories of VTE. Now, French investigators retrospectively assessed the effects of oral and transdermal estrogen on risk for recurrent VTE in 1023 postmenopausal women (age range, 45–70) with prior confirmed first VTE.
     Overall, 130 women used hormone therapy after first VTE; of these, 103 used transdermal estrogen and 10 used oral estrogen. Seventy-seven women experienced recurrent VTE during a mean of 79 months after discontinuing anticoagulant therapy. After adjustment for several potential confounders, no significant association was found between recurrent VTE and use of transdermal estrogen (hazard ratio, 1.0) compared with nonuse. But women who used oral estrogen had significantly increased risk (HR, 6.4).
     Comment: This provocative — but far from definitive — study is limited by inadequate dosing information and small size (recurrent VTE occurred in only 2 and 6 users of oral and transdermal estrogen, respectively). Nonetheless, the results provide additional evidence that VTE risk might differ with route of estrogen administration. The findings also suggest that transdermal estrogen (preferably at low doses) might be considered with caution for women with prior VTE who have intractable menopausal symptoms. As an editorialist notes, use of transdermal estrogen might also be extended to include symptomatic postmenopausal women who have substantial risk factors for thrombosis.
Robert W. Rebar, MD
Published in Journal Watch Women's Health June 16, 2011
     Citation(s):Olié V et al. Hormone therapy and recurrence of venous thromboembolism among postmenopausal women. Menopause 2011 May; 18:488. http://www.ncbi.nlm.nih.gov/pubmed/21178641?dopt=Abstract
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Diet Drinks Added Fat, Aspartame Made Mice Diabetic
Expanded waistlines in people, higher glucose levels in mice hint at artificial sweeteners' lack of benefit and possible counterproductive effects
by Craig Weatherby
Chalk up two more losses for artificial sweeteners in the realms of obesity and diabetes research. We covered just a bit of the large body of worrying evidence about aspartame and its chemical cousins, in “Artificial Sweetener Raises Lifelong Concerns”.
     Now, the results of a population study and a mouse trial further undermine the presumed but unproven weight-control and diabetes-deterrence value of diet drinks and a common non-caloric sweetener. In the constant battle of the bulge, many reach for artificially sweetened diet sodas as substitutes for sugary beverages, which contribute a whopping 20 percent of the calories in the average American’s diet (see “The Calories We Quaff”). But two studies presented last month at the American Diabetes Association's Scientific Sessions in San Diego suggest this might be a self-defeating strategy.
     Scientists from The University of Texas Health Science Center San Antonio linked diet soft drinks to bigger waistlines in people … and a second study found that aspartame raised fasting glucose (blood sugar) levels in diabetes-prone mice. According to co-author Helen P. Hazuda, Ph.D., “Data from this and other prospective studies suggest that the promotion of diet sodas and artificial sweeteners as healthy alternatives may be ill-advised. They may be free of calories but not of consequences.” (UT 2011)

Human study disses diet sodas
     The Health Science Center team analyzed data from 474 participants in the San Antonio Longitudinal Study of Aging, or SALSA … a large, 20-year-long study among elderly Mexican Americans and European Americans (Fowler SP, Williams K, Hazuda HP 2011).  Measures of height, weight, waist circumference, and diet soda intake were recorded when people enrolled in the SALSA study, and at three follow-up exams that took place over the next decade. The researchers compared long-term changes in waist circumference for diet soda users versus non-users, and adjusted the results for diet and lifestyle factors affecting weight gain or loss.
     Overall, the diet soft drink users experienced 70 percent greater increases in waist circumference compared with non-users. Frequent users, who said they consumed two or more diet sodas a day, experienced waist circumference increases that were 500 percent greater than those of non-users. Abdominal fat is a major risk factor for diabetes, cardiovascular disease, cancer, and other chronic conditions. As the authors wrote, “These results suggest that, amidst the national drive to reduce consumption of sugar-sweetened drinks, policies that would promote the consumption of diet soft drinks may have unintended deleterious effects.” (UT 2011)

Aspartame consumption raises blood sugar in diabetes-prone mice
     In a related study, University of Texas researchers studied the relationship between aspartame intake and blood levels of fasting glucose and insulin in 40 diabetes-prone mice (Fowler SP, Halada GV, Fernandes G. 2011). Aspartame is the common artificial sweetener widely used in diet sodas and other products.One group of the mice ate chow to which both aspartame and corn oil were added; the other group ate chow with the corn oil added but not the aspartame. After three months on this high-fat diet, the mice in the aspartame group showed elevated fasting glucose levels but equal or diminished insulin levels. These twin changes are associated with early declines in the functioning of pancreatic beta cells, which produce insulin to get blood sugar into cells, which also lowers blood sugar levels after a meal.

Senior author Gabriel Fernandes, Ph.D., made a key point:
     “These results suggest that heavy aspartame exposure might potentially directly contribute to increased blood glucose levels, and thus contribute to the associations observed between diet soda consumption and the risk of diabetes in humans.” (UT 2011) Both studies were funded by the Institute for the Integration of Medicine and Science (IIMS), which oversees the university's Clinical and Translational Science Award (CTSA). This National Institutes of Health-funded program encourages the rapid translation of scientific discoveries from the laboratory to policies and practical applications for public health.

University of Texas Health Science Center at San Antonio (UT). Related studies point to the illusion of the artificial. June 27, 2011. Accessed at http://www.eurekalert.org/pub_releases/2011-06/uoth-rsp062711.php
Fowler SP, Williams K, Hazuda HP. Diet Soft Drink Consumption Is Associated with Increased Waist Circumference in the San Antonio Longitudinal Study of Aging. Abstract No. 0062-OR. Accessed at http://ww2.aievolution.com/ada1101/index.cfm?do=abs.viewAbs&abs=10061. American Diabetes Association 71st Scientific Sessions, June 24 - 28, 2011, San Diego Convention Center - San Diego, California
Fowler SP, Halada GV, Fernandes G. Aspartame Consumption Is Associated with Elevated Fasting Glucose in Diabetes-Prone Mice. Abstract No. 0788-P. Accessed at http://ww2.aievolution.com/ada1101/index.cfm?do=abs.viewAbs&abs=10845. American Diabetes Association 71st Scientific Sessions, June 24 - 28, 2011, San Diego Convention Center - San Diego, California   
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JAMA 2011 Jun 1; 305:2184
Predicting Fracture Risk in Patients with Type 2 Diabetes
At similar bone-mineral densities, fracture risk was higher for diabetic patients.
     Type 2 diabetes mellitus is associated with both higher bone-mineral density (BMD) and, paradoxically, higher fracture risk. Normative values for BMD, or other standardized risk assessments, such as the WHO Fracture Risk Algorithm (FRAX) score, might not perform well in diabetic patients. Data from three national prospective cohort studies were combined to assess fracture risk in 9449 older women (median follow-up, 12.6 years) and 7436 older men (median follow-up, 7.5 years). Among 770 diabetic women, 262 suffered nonspine fractures; among 1199 diabetic men, 133 suffered nonspine fractures. About one quarter of reported fractures were hip fractures.
     Age- and sex-adjusted BMD (T-score) predicted fracture risk similarly for participants with or without diabetes. However, at any given T-score, diabetic patients were at higher risk than nondiabetic participants: Diabetic women with T-scores that were 0.59 units higher (i.e., less negative) than nondiabetic women of the same age had similar hip fracture risk; the corresponding value for men was 0.38 units. Similar relations were noted for FRAX scores.
     Comment: These results confirm that BMD T-score and FRAX score are useful predictors of hip and nonspine fracture risks in patients with or without diabetes. However, any given T-score or FRAX score is associated with higher fracture risk in a patient with type 2 diabetes than in a patient without diabetes. Further refinement of these values, as they apply to older diabetic patients, would be helpful.
Thomas L. Schwenk, MD Published in Journal Watch General Medicine June 28, 2011
     Citation(s): Schwartz AV et al. Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes. JAMA 2011 Jun 1; 305:2184. (http://dx.doi.org/10.1001/jama.2011.715)
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Smoking During Pregnancy Linked to Increased Risk for Birth Defects
     Maternal smoking during pregnancy is associated with increased risks for a wide variety of birth defects, according to a meta-analysis in Human Reproduction Update.
Researchers examined some 100 studies comprising nearly 175,000 birth defect cases and more than 11.5 million unaffected controls. They found that maternal smoking was tied to significantly increased risks for certain types of birth defects, including:

     The authors conclude: "These specific defects should be included in ... educational information to encourage more women to quit smoking before or early on in pregnancy, and to particularly target younger women and those from lower socioeconomic groups, in which smoking prevalence is greatest."
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Don't Miss the New AHA Recommendations on Triglycerides
A new scientific statement raises the threshold for pharmacologic treatment of hypertriglyceridemia.
     The following was published as a "Voices" blog on CardioExchange, an online forum for cardiology news and discussion. The blog prompted a lively conversation, which you can access and join by registering for CardioExchange.
     I've been surprised at the lack of fanfare surrounding the American Heart Association's recently published scientific statement on triglycerides and cardiovascular disease (CVD). The attention it did receive focused on the lower fasting triglyceride level that is now considered optimal: <100 mg/dL. In my opinion, the real headline was the committee's important statements in support of less drug treatment — in particular, the recommendation for a substantial increase in the triglyceride level that should trigger consideration of pharmacologic therapy.
     After a careful review of the recent literature, the committee concluded that pharmacologic therapy should not be started until a patient's fasting triglyceride level is ≥500 mg/dL (in contrast to the Adult Treatment Panel's recommendation of ≥200 mg/dL). See the figure, which also appears on page 2308 of the AHA statement.
     The AHA committee also explicitly acknowledges (on page 2297) that "the independence of triglyceride level as a causal factor in promoting CVD remains debatable. Rather, triglyceride levels appear to provide unique information as a biomarker of risk, especially when combined with low HDL-C and elevated LDL-C." This clear statement — together with the new, higher threshold for initiating drug treatment — represents a remarkable change.
Meanwhile, on April 20, Abbott announced that sales of its flagship fenofibrate drugs increased by 28% in the first quarter.

Two questions:

I welcome your insights.
Harlan M. Krumholz, MD, SM Published in Journal Watch Cardiology July 13, 2011
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Circulation 2011 May 24 ; 123:2292
Triglycerides and Cardiovascular Disease: The Experts Speak
Experts redefine an optimal triglyceride level and stress that lifestyle changes are required to reach it.
     While debate continues about whether hypertriglyceridemia independently predicts coronary artery disease, mean triglyceride levels in the U.S. are rising, along with rates of obesity and diabetes. In a new scientific statement, the American Heart Association (AHA) outlines the scope of the problem and offers treatment recommendations. Triglyceride levels directly influence high- and low-density lipoprotein metabolism, and hypertriglyceridemia can be mediated genetically or acquired (e.g., in patients with hypothyroidism, diabetes, or renal disease).
     The authors propose a "practical algorithm" for initial screening with nonfasting triglyceride measurement. If levels are <200 mg/dL (corresponding to <150 mg/dL on a fasting sample), they suggest that patients continue with healthy diet and activity levels. At levels ≥200 mg/dL, fasting lipoprotein measurement is advised, and suggested targets are provided for weight loss and intake of dietary carbohydrates, sugars, and fats. Increased physical activity and intake of {omega}-3 fatty acids also are advocated for their profound effects on elevated triglyceride levels. At the highest triglyceride levels or in symptomatic patients, pharmacologic therapy can be useful (e.g., to lower risk for pancreatitis in patients with triglycerides >500 mg/dL). At all triglyceride levels, the AHA recommends avoiding consumption of trans fats, which raise triglyceride levels and atherogenic lipid particles. Finally, the guidelines set <100 mg/dL as an optimal triglyceride level.
     This statement summarizes what we know about triglycerides and their relation to disease and provides a framework for treating the many patients with suboptimal triglyceride levels (see JW Cardiol Jul 13 2011 for additional commentary from Harlan Krumholz). Patients should be advised that lifestyle changes in diet, weight loss, and exercise are basic to treating most cases of hypertriglyceridemia, although tightening the definition of an optimal triglyceride level could inadvertently invite additional prescribing.
— Kirsten E. Fleischmann, MD, MPH
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AN ADDITIONAL PERSPECTIVE FROM the Journal Watch general medicine EDITOR-in-chief:
     In this AHA-sponsored statement, the authors acknowledge that the evidence for triglycerides as an independent predictor of cardiovascular events (i.e., after adjustment for other lipid fractions) remains controversial. They also acknowledge the lack of convincing clinical-trial evidence to support triglyceride-lowering drug therapies, independent of LDL-cholesterol–lowering or statin therapy; indeed, no benefit was seen in the recent AIM-HIGH study. Hence, this statement is somewhat self-contradictory: If drugs are not indicated (except to lower risk for pancreatitis when triglycerides are extremely elevated), and if lifestyle modifications that happen to lower triglycerides are worthwhile regardless of triglyceride levels, why should we closely monitor triglyceride levels? I am unaware of evidence that patients who track their triglyceride levels are more motivated to exercise, lose weight, and eat a heart-healthy diet than are patients who receive similar counseling without following triglycerides. A move to more-intense focus on triglyceride levels, and to a more stringent definition of "optimal" triglycerides, thus seems unnecessary and misguided.
— Allan S. Brett, MD
Miller M et al. Triglycerides and cardiovascular disease: A scientific statement from the American Heart Association. Circulation 2011 May 24 ; 123:2292.
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Clin Infect Dis 2011 Jul 1; 53:42.
Cumulative Antibiotic Exposure Is Associated with Risk for C. difficile Infection
In a retrospective study among hospitalized patients, higher cumulative dose, number, and duration of antibiotics were independently associated with greater risk.
     Antibiotic therapy is a major risk factor for Clostridium difficile infection (CDI), but little is known about the effect of cumulative exposure. To explore this issue, researchers performed a retrospective cohort study involving adults who were hospitalized at a Rochester, New York, medical center in 2005 and received antibiotics for ≥2 consecutive days during their stay.
     For each day of antibiotic exposure, the total dose of each agent was calculated. Daily doses were standardized according to the WHO Defined Daily Dose system. The number of different antibiotics and the duration of exposure were also calculated.
A total of 10,154 hospitalizations involving 7792 unique patients met study criteria. The incidence of CDI in this group was 4.3 per 10,000 patient-days. Factors significantly associated with increased CDI risk included older age, gastrointestinal procedures, HIV infection, history of CDI, higher chronic disease score, longer length of stay, and receipt of antacid therapy ,including proton-pump or histamine-2 inhibitors. In addition, CDI risk rose, in a dose-dependent manner, with increases in cumulative dose, number, and days of antibiotics. Risk was 7.8-fold higher in patients with >18 antibiotic days than in those with <4 days and 9.6-fold higher in patients who received five or more antibiotics than in those who received only one. Intravenous cephalosporins, β-lactamase inhibitor combinations, sulfa drugs, fluoroquinolones, and vancomycin were all associated with an increased risk for CDI.
     Comment: These findings suggest that longer durations of therapy and increasing numbers of antibiotics are associated with heightened risk for CDI. One surprising outcome is that vancomycin — a therapy for CDI when given orally — is a risk factor when administered intravenously.
Neil M. Ampel, MD Published in Journal Watch Infectious Diseases July 13, 2011
     Citation(s): Stevens V et al. Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. Clin Infect Dis 2011 Jul 1; 53:42.
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Newer Prostate Cancer Drugs Add Months to Life — at High Cost
     Patients may be asking about a New York Times article examining the impact of newer drugs for advanced prostate cancer.
     The drugs, all approved by the FDA within the past 2 years, provide definite — if modest — survival benefits (all add 2 to 5 months to median survival times). They are also very expensive — a typical course of treatment can range from roughly $20,000 to $90,000. Drug companies, according to the report, seem to be following each other's leads to ever-higher prices.
     The Times quotes one drug executive as telling securities analysts that "the pricing environment is encouraging and getting better for us." Annual revenues from some drugs are expected to reach $1 billion. Since the drugs are used almost exclusively in older people, Medicare could be footing much of the bill.
According to the Times, Medicare is expected to announce on Thursday whether it will cover Provenge (sipuleucel-T), which, at $93,000, is the most expensive of the newer treatments
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JAMA 2011 Jun 22/29; 305:2548
Smoking Increases the Risk for Prostate Cancer Recurrence and Mortality
The increase in risk was seen only among men who were current or recent smokers at the time of diagnosis.
     Several studies have suggested that cigarette smoking increases the risk for prostate cancer mortality, but most of these studies were relatively small. Now, researchers have evaluated this association as well as the link between smoking and prostate cancer recurrence in a large U.S. prospective cohort study (the Health Professionals Follow-Up Study).
     More than 50,000 men were enrolled in the cohort in 1986 and asked to complete detailed questionnaires every 2 years about various lifestyle factors, including current and past cigarette use, and any new medical diagnoses. The present analysis focused on 5366 men who reported prostate cancer diagnoses between 1986 and 2006.
     During follow-up, there were 878 biochemical recurrences (defined by an increase in prostate-specific antigen [PSA] levels) and 524 deaths due to prostate cancer. The absolute crude rate of prostate cancer–specific death per 1000 person-years was 9.6 for men who had never smoked versus 15.3 for those who were smokers at the time of diagnosis; the corresponding all-cause mortality rates were 27.3 and 53.0 per 1000 person-years.
     In a multivariate analysis, the risks for biochemical recurrence and disease-specific mortality were significantly higher for men who were smokers at the time of diagnosis than for those who had never smoked. Being exposed to a greater number of pack-years was associated with significantly increased risk for prostate cancer mortality but not for biochemical recurrence. Men who had quit smoking ≥10 years prior to diagnosis — or who had quit more recently but smoked for <20 pack-years — had prostate cancer–mortality risks similar to those of men who had never smoked.
     Comment: For men who undergo definitive local therapy for prostate cancer, PSA recurrence has both clinical and psychological implications, the latter of which is often more consequential to the patient. For those patients who continue to smoke, this study might provide additional inducement to help them stop.
Robert Dreicer, MD, MS, FACP Published in Journal Watch Oncology and Hematology June 28, 2011
     Citation(s):Kenfield SA et al. Smoking and prostate cancer survival and recurrence. JAMA 2011 Jun 22/29; 305:2548.
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Lancet 2011 Jul 9; 378:156
Intensified Early Treatment of Subclinical Diabetes: No Benefit at 5 Years
Longer follow-up might reveal benefit.
     Clinicians often diagnose type 2 diabetes by screening asymptomatic patients, but how intensively patients should be managed at this early stage of disease is unclear.
Researchers in the U.K., Denmark, and the Netherlands randomized 343 primary care practices to provide either routine care or intensive multifactorial treatment to 3057 patients with early diabetes that was diagnosed through routine screening. Physicians and nurses in the intensive intervention received education on targets, algorithms, and lifestyle advice for managing hyperglycemia, blood pressure, and lipids; in some areas, patients also met periodically with diabetes nurses.
     After a mean follow-up of 5.3 years, mean declines in levels of glycosylated hemoglobin (HbA1c), total and LDL cholesterol, and blood pressure were slightly but significantly greater in patients in the intensive treatment practices than in those receiving routine care. The incidence of the primary composite endpoint (cardiovascular death, nonfatal myocardial infarction or stroke, or revascularization), each of its components, and all-cause death was lower in the intensive treatment group. However, none of these differences in clinical outcomes reached significance (hazard ratio for composite endpoint, 0.83; P=0.12).
     Comment: Although this trial had the virtue of a pragmatic setting, it took place against the background of improving evidence- and guideline-driven general diabetes care, which might have lessened the relative effect of the intensive intervention. The cumulative incidence curves for the primary endpoint began to diverge after 4 years; longer follow-up might reveal an important clinical benefit.
Bruce Soloway, MD Published in Journal Watch General Medicine July 12, 2011
     Citation(s):Griffin SJ et al. Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): A cluster-randomised trial. Lancet 2011 Jul 9; 378:156. (http://dx.doi.org/10.1016/S0140-6736(11)60698-3)
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Ann Neurol 2011 Jun; 69:1043
Painless Diabetic Motor Neuropathy
In this unusual condition, muscle weakness is more prominent than sensory symptoms.
     Diabetes typically causes a symmetric, distal, predominantly sensory neuropathy. Much less common is diabetic amyotrophy, an often asymmetric, relatively acute, painful neuropathy dominated by lower-limb muscle weakness. This condition — also called diabetic lumbosacral radiculoplexus neuropathy (DLRPN) — is thought to reflect ischemic microvascular injury that affects nerve roots and peripheral nerves. Now, Mayo Clinic researchers present 23 diabetic patients (22 with type 2 diabetes) who had a painless variant of this disorder, which they call "painless diabetic motor neuropathy."
     Median duration of diabetes was 5 years, but the neurological presentation coincided with a first recognition of diabetes in seven cases. Glycemic control was generally excellent. Most patients exhibited substantial weight loss as their neurological illness evolved. The most common presentation was subacute development of bilateral foot drop, with later involvement of proximal leg muscles and with lesser involvement of upper extremities. Although onset was initially unilateral in one third of cases, involvement usually became bilateral. In contrast, painful DLRPN generally presents unilaterally and more rapidly, with greater involvement of proximal than distal leg muscles. Based on nerve biopsies, nerve conduction studies, electromyography, and clinical characteristics, the authors conclude that painless diabetic motor neuropathy is a variant of painful DLRPN, and not a separate entity.
     Comment: Although only a small proportion of diabetic patients develop diabetic motor neuropathies, diabetes is so common that primary care clinicians will occasionally encounter these cases. Most patients improve gradually.
Allan S. Brett, MD Published in Journal Watch General Medicine July 12, 2011
     Citation(s): Garces-Sanchez M et al. Painless diabetic motor neuropathy: A variant of diabetic lumbosacral radiculoplexus neuropathy? Ann Neurol 2011 Jun; 69:1043. (http://dx.doi.org/10.1002/ana.22334)
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J Clin Oncol 2011 Jun 13
Breast-Conserving Therapy vs. Mastectomy for Triple-Negative Breast Cancer
In women with T1-2N0 TNBC, risk for local regional recurrence was lower after lumpectomy plus radiotherapy than after modified radical mastectomy.
     Triple-negative breast cancer (TNBC; negative for estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2) is associated with unfavorable prognosis, in part because of poor response to systemic therapies and radiotherapy as well as high rates of local regional recurrence (LRR; J Clin Oncol 2006; 24:5652 and J Clin Oncol 2008; 26:1419). In a retrospective cohort study involving 768 patients with TNBC in Alberta, Canada, researchers evaluated LRR-free survival following breast-conserving therapy (BCT; lumpectomy and adjuvant radiation therapy [RT]) or modified radical mastectomy (MRM) with or without RT; in a subgroup of 468 patients with T1-2N0 TNBC, outcomes following BCT or MRM were compared.
     At median follow-up of 7.2 years, 5-year LRR-free survival was 94%, 85%, and 87% in the BCT, MRM, and MRM plus RT groups, respectively (P<0.001). Multivariate analysis showed that receipt of MRM (compared with BCT) was associated with excess risk for LRR and that adjuvant chemotherapy was associated with lower risk for LRR. Among patients with T1-2N0 tumors, 5-year LRR-free survival was 96% versus 90% in the BCT and MRM groups, respectively (P=0.022), and MRM was the only independent prognostic factor associated with excess risk for LRR (hazard ratio, 2.53; P=0.026). Local regional management was not found to be an independent prognostic factor for overall survival.
     Comment: In their assessment of risk for local regional recurrence associated with breast-conserving therapy or mastectomy for triple-negative breast cancer, these authors have added important insights about management of this aggressive form of cancer. By showing that patients with T1-2N0 TNBC who undergo modified radical mastectomy without radiotherapy have higher risk for LRR than do patients who receive BCT, the results are controversial because they imply that some patients with TNBC might be better served with BCT than with MRM — and that patients with T1-2N0 TNBC who undergo mastectomy should subsequently receive RT. Although patients in the T1-2N0 subgroup had similar clinical pathology whether they received MRM or BCT, unrecognized selection biases might have occurred such that patients who underwent MRM had more-advanced disease. Nonetheless, the findings are provocative and point to the need for prospective studies evaluating risk for LRR in TNBC patients following mastectomy with or without RT. The study provides no data to support routine use of postmastectomy RT in patients with T1-2N0 TNBC, consistent with long-term data suggesting that this subtype of breast cancer exhibits a relatively high degree of radioresistance.
Henry Mark Kuerer, MD, PhD, FACS Published in July 12, 2011
     Citation(s): Abdulkarim BS et al. Increased risk of locoregional recurrence for women with T1-2N0 triple-negative breast cancer treated with modified radical mastectomy without adjuvant radiation therapy compared with breast-conserving therapy. J Clin Oncol 2011 Jun 13; [e-pub ahead of print]. (http://dx.doi.org/10.1200/JCO.2010.33.4714)
Pignol J-P et al. Is breast conservation therapy superior to mastectomy for women with triple-negative breast cancers? J Clin Oncol 2011 Jun 13; [e-pub ahead of print]. (http://dx.doi.org/10.1200/JCO.2011.35.8838)
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JAMA 2011 Jun 8; 305:2295.
Ovarian Cancer Screening: No Advantage
Annual screening based on CA 125 and vaginal ultrasound was ineffective, and diagnostic follow-up was risky.
     Ovarian cancer is highly lethal because symptoms are slow to emerge and late-stage diagnosis therefore is common; accordingly, clinicians often are asked about screening. From late 1993 through mid-2001, U.S. investigators for the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial randomized 78,216 women (age range, 55–74) to annual screening with serum cancer antigen (CA) 125 testing plus vaginal ultrasound or to usual care. Positive screens were defined by CA 125 levels ≥35 U/mL or abnormal ultrasound findings. In 2009, PLCO results showed that screening had low positive predictive value (JW Womens Health Apr 16 2009). Now, PLCO investigators report effects of screening on ovarian cancer mortality.
     The proportion of screen-detected cancers that were late-stage was only slightly lower than the proportion of cancers detected at late stages during usual care (69% and 78%, respectively). Ovarian cancer deaths occurred in 118 and 100 women in the screening and usual-care groups, respectively (ovarian cancer death rates, 3.1 and 2.6 per 10,000 person-years). Of 3285 women with false-positive screening results, 1080 underwent surgical follow-up; 163 of these women (15%) experienced one or more serious complications.
     Comment: The authors note that their discouraging findings might reflect the rapid progression of aggressive ovarian tumors, making detection with annual screening ineffective. Moreover, some screen-detected tumors might never have been destined to cause clinical problems. Finally, the serious perioperative complications associated with follow-up of false-positive screening results are sobering. Although effective screening approaches might emerge someday, the findings of the PLCO trial should strengthen our current resolve to "just say no" to ovarian cancer screening.
Andrew M. Kaunitz, MD Published in Journal Watch Women's Health June 16, 2011
     Citation(s):Buys SS et al. Effect of screening on ovarian cancer mortality: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA 2011 Jun 8; 305:2295.
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Viewing TV, Computers or Video Games Before Bedtime and Watching Violent Content Affect Kids' Sleep
     Preschoolers who watch violent content or view television before bedtime have more sleep problems, according to a Pediatrics study.
Researchers assessed media usage and sleep habits among roughly 600 preschool-aged children via surveys and media diaries. They found that children who used television, computers, or video games after 7 p.m. reported more sleep issues (e.g., repeated night wakings, nightmares, daytime tiredness). Watching violent content any time of day also was associated with sleep problems.
     Children with televisions in their bedrooms watched more violent content and were more likely to have sleep problems.
     The authors conclude: "Pediatricians can advise parents to focus on reducing violent content and evening media use, which may be both more acceptable and feasible for families living in the digital age than focusing on a global reduction or elimination of media use. For families reluctant to change their child's media use, discussion about the impact on sleep may increase parental motivation."
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MM: Ok, autoantibodies may be a risk factor  for miscarriage but is giving levothyroxine (T4) the answer? I believe not. Look at iodine levels and assess if there is a deficiency first. This is frequently a potential source of the issue, not T4 deficiency. T4 deficiency is the sympton, not the illness.
BMJ 2011 May 9; 342:d2616
Thyroid Autoantibodies and Excess Risk for Miscarriage and Preterm Birth
Pregnant women with thyroid autoantibodies might warrant treatment with levothyroxine, even if they have normal thyroid function.
     The presence of thyroid autoantibodies is relatively common in women of reproductive age, even among those with normal thyroid function. To estimate the association between these autoantibodies and risk for miscarriage or preterm birth, researchers conducted a systematic review and meta-analysis of 19 cohort studies and 12 case-control studies that involved more than 12,000 women.
     Thyroid autoantibodies were associated with excess risk for miscarriage (odds ratio, 3.9; P<0.001) and preterm birth (OR, 2.1; P=0.01). Although miscarriage rates generally rise as women age, the observed excess in miscarriage rates among women with thyroid autoantibodies was not explained by differences in maternal age. Pooled analysis of two randomized trials that involved 160 women who had autoantibodies but normal thyroid function showed that treatment with levothyroxine lowered risk for miscarriage (relative risk, 0.48; P=0.03).
     Comment: No adverse maternal or fetal effects of levothyroxine were identified in the studies reviewed by these authors, but statistical power to identify uncommon events was limited; thus, a larger study on the effect of levothyroxine on pregnancy outcomes would be helpful in confirming the safety and efficacy of this treatment for women with thyroid autoantibodies.
Eleanor Bimla Schwarz, MD, MS Published in Journal Watch Women's Health June 9, 2011
     Citation(s):Thangaratinam S et al. Association between thyroid autoantibodies and miscarriage and preterm birth: Meta-analysis of evidence. BMJ 2011 May 9; 342:d2616.
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J Clin Oncol 2011 May 9;
BMI and Efficacy of Endocrine Therapy for Premenopausal Breast Cancer
Efficacy of an aromatase inhibitor plus goserelin was compromised in patients with high body-mass index.
     For hormone receptor–positive breast cancer, up-front therapy with an aromatase inhibitor (AI) is an appealing option in premenopausal women who undergo ovarian suppression. In such women (as well as in postmenopausal women), estrogen is derived primarily from aromatization of steroid precursors in adipose tissue, raising the question of whether body-mass index (BMI) influences endocrine treatment outcomes. In an Austrian trial, 1684 premenopausal women (one third of whom were overweight [BMI, 25.0–29.9 kg/m2] or obese [BMI, ≥30.0]) who had hormone receptor–positive breast cancer received the gonadotropin releasing hormone (GnRH) agonist goserelin for ovarian suppression and were randomized to either tamoxifen or the AI anastrozole.
     At median follow-up of 63 months, disease-free survival (as well as overall survival) was similar in the two treatment groups for normal-weight women. However, overweight women who received anastrozole had 49% higher risk for disease recurrence (not statistically significant) and threefold higher risk for breast-cancer–related death (P=0.004) than did those who received tamoxifen.
     Comment: The authors hypothesize that conventional doses of AI therapy might not adequately suppress serum estrogen levels in obese women, and also that conventional doses of GnRH therapy might not completely suppress ovarian function in premenopausal obese women. Both of these possibilities point to the need for dose-ranging studies of ovarian suppression combined with AI treatment for obese women with premenopausal hormone receptor–positive breast cancer. In general, high BMI compromises outcomes in women with breast cancer (JW Womens Health Dec 22 2010); therefore, weight loss and physical activity should be encouraged whenever possible.
Andrew M. Kaunitz, MD Published in Journal Watch Women's Health June 9, 2011
     Citation(s):Pfeiler G et al. Impact of body mass on the efficacy of endocrine therapy in premenopausal patients with breast cancer: An analysis of the prospective ABCSG-12 trial.
J Clin Oncol 2011 May 9; [e-pub ahead of print].
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