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NEJM Journal Watch

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After hearing and assimilating this program, the listener will be better able to: ( 1 ) Increase his/her basic knowledge of important advances in medicine; ( 2 ) Identify a broad range of clinical research reported in the medical literature; ( 3 ) Synthesize research findings through one-on-one interviews with authors and editorialists; ( 4 ) Integrate new treatments reviewed in the summaries into current practice; ( 5 ) Challenge oneself with thoughtful, clinically relevant questions. Disclosure In adherence to the ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, Dr. Allan Brett, Dr. Meir Stampfer, and the planning committee members reported that they had nothing to disclose. GUIDELINE WATCH: USPSTF RECOMMENDATIONS ON INTERVENTIONS FOR SMOKINGCESSATION Approximately 18% of the adults in the United States smoke tobacco, and tobacco remains the leading preventable cause of morbidity and mortality. In the October20 Annals of Internal Medicine ( http:// dx.doi.org /10.7326/M15-2023 ), the United States Preventive Services Task Force has updated its 2009 guidelines on counseling and interventions to prevent the use of tobacco ( www.jwatch.org /jw200905070000002 ). Key recommendations from the update are: Record a patients smoking behavior as a vital sign. Use the 5 A s, which are: 1. A sk about smoking. 2. A dvise patients to quit through personalized messages. 3. A ssess a patients willingness to quit. 4. A ssist the quitting process. 5. A rrange follow-up. With regard to interventions for nonpregnant adults: Convincing evidence shows that behavioral interventions (like counseling and self-help materials) improve cessation; added to pharmacotherapy, they improve cessation rates by about 5%. Convincing evidence shows that nicotine replacement therapy (patches, lozenges, gum, inhalers, and nasal spray) improves cessation rates (from 10% to 17%). Bupropion SR and varenicline, with or without behavioral counseling, improve cessation rates (by approximately 8% with bupropion and 16% with varenicline). Concurrently using two types of nicotine replacement therapy improves cessation rates relative to using one, and nicotine replacement therapy adds benefit to bupropion alone. The evidence was insufficient to evaluate the use of electronic nicotine delivery systems as a smoking cessation tool in adults and adolescents. With regard to interventions for pregnant women: Behavioral interventions improve cessation rates. The evidence is inadequate to recommend nicotine replacement therapy, and no evidence exists on bupropion SR, varenicline, or electronic nicotine delivery systems. This guideline on interventions for tobacco smoking cessation provides a useful overview of best practices toward achieving the difficult goal of abstinence ( http:// dx.doi.org /10.7326/M15-0171 ). One point in the guideline that might be unfamiliar to clinicians is that the concurrent use of two nicotine-replacement modalities improves cessation rates compared with using a single modality. Whereas the United States Preventive Services Task Force finds insufficient evidence to provide a recommendation on e-cigarettes as smoking cessation aids, the American Heart Association has issued tentative support for e-cigarettes when other methods have failed ( http:// dx.doi.org /10.1161/CIR.0000000000000107 ). NEW EMPHASIS ON AMBULATORY AND HOME BP MONITORING In an update of a guideline published back in 2007, the United States Preventive Services Task Force has reaffirmed its recommendation that adults should be screened for high blood pressure ( www.jwatch.org /jw200801080000002 ). Thats not particularly newsworthy, but the new statement has an important addition: It recommends that clinicians measure blood pressure outside of the clinical setting to confirm the diagnosis of hypertension before starting treatment. Details appear on the website of the Annals of Internal Medicine ( http:// dx.doi.org /10.7326/M15-2223 ). The authors of the recommendation statement prefer ambulatory blood pressure monitoring, in which the patient wears a device that typically records blood pressure every 30minutes for 24hours. When ambulatory blood pressure monitoring isnt available, home blood pressure measurements taken with a standard home blood pressure unit are an acceptable alternative. A review of the literature showed that most of the discordance between in-office and out-of-office measurements is in the direction of higher office readings, potentially resulting in overdiagnosis and overtreatment if clinicians rely solely on in-office measurements. Studies show that both ambulatory and home blood pressure are independent predictors of adverse cardiovascular outcomes, after adjusting for office blood pressure. Many clinicians already use patients home blood pressure measurements both to corroborate a diagnosis of hypertension and to adjust antihypertensive therapy. Twenty-fourhour ambulatory blood pressure monitoring is used less commonly for a number of reasons (like a lack of availability and concerns about cost and insurance coverage), but the new United States Preventive Services Task Force recommendation will probably result in an increase in the use of ambulatory blood pressure monitoring. Its important to mention that the out-of-office confirmation of hypertension is not necessary for patients with multiple severely elevated blood pressure readings in the office or in the hospital. The Annals of Internal Medicine has also published a narrative review online ( http:// dx.doi.org /10.7326/M15-1270 ) that provides additional details on ambulatory and home monitoring. SHOULD THE PREPUBLICATION SPRINT RESULTS AFFECT CLINICAL PRACTICE RIGHT NOW? Lets wait until the complete findings are published. On September14, 2015, one of my patients called the office and asked whether we should intensify her antihypertensive drug regimen. She is a 90-year-old, independently living woman who takes one antihypertensive drug; her typical blood pressure (BP) is around 150/75mmHg, but, in recent years, her systolic BPs have been as low as 130mmHg and as high as 170mmHg. What prompted the call? She had watched the evening news and had heard about the just-announced result of the Systolic Blood Pressure Intervention Trial (SPRINT https:// www. sprinttrial .org ) sponsored by the National Institutes of Health (NIH). That week, many other patients called our practice with the same question or mentioned the trial during office visits. Thus, a quick review of SPRINT is appropriate. In SPRINT, more than 9000 patients with hypertension were randomized to intensive treatment (systolic BP goal, 120mmHg) or standard treatment (systolic BP goal, 140mmHg). Patients were eligible if they were 50 or older, were hypertensive, and had at least one other risk factor; the latter included known clinical or subclinical cardiovascular disease other than stroke, chronic kidney disease (estimated glomerular filtration rate, 20-59 mL/minute /1.73 m 2 ), Framingham 10-year risk score of at least 15%, or age >75. Notably, patients with diabetes were excluded, because the previously published ACCORD study had shown no advantage for more-intensive treatment in diabetic patients ( www.jwatch.org /jw200806060000001 ). On September11, 2015, an NIH press release ( www. nih .gov /news/health/sep2015/nhlbi-11.htm ) announced that SPRINT had been stopped early because of a clear advantage for the intensively treated group. The NIH stated that more-intensive treatment reduced rates of cardiovascular events by almost a third and the risk of death by almost a quarter . However, because the full results of the trial have not been published yet, applying them to patient care remains problematic for now. For example, the relative reductions in adverse cardiovascular events and mortality have been announced, but we dont know the absolute reductions (or the number needed to treat to benefit one patient). We dont know whether specific drug categories were more (or less) beneficial than others. We also dont know yet whether the intensively treated group experienced substantial adverse effects (e.g., symptomatic hypotension) that would make intensive treatment less desirable in certain patient subgroups. We await the findings on whether older patients (e.g., age, ≥75) benefit to the same extent as younger patients. Dr. Harlan Krumholz, Editor-in-Chief of NEJM Journal Watch Cardiology joined by Dr. Eric Topol wrote in the New York Times (on September17, 2015 www. nytimes .com /2015/09/18/opinion/dont-delay-news-of-medical-breakthroughs.html ) that without knowing all this information, it is not possible for doctors and patients to know how to translate these findings into action . I agree with their position. So, how did I respond to my patient? As it turned out, she would not have been eligible for SPRINT because she has diabetes (although her diabetes is mild and diet controlled). Plus, she has been plagued for years by vague undiagnosed dizziness , and I would think twice before prescribing additional drugs to patients like her. I look forward to seeing the full published results of SPRINT; until then, I will continue to prescribe according to currently accepted standards for BP control. Allan Brett, MD CAN WE PREDICT TREATMENT RESPONSE IN PATIENTS WITH RESISTANT HYPERTENSION AND SLEEPAPNEA? Often, patients with resistant hypertension have concomitant obstructive sleep apnea, but blood pressure response to treatment with continuous positive airway pressure in these patients is highly variable. In a study in the September1 Journal of the American College of Cardiology ( http:// dx.doi.org /10.1016/ j. jacc.2015.06.1315 ), researchers in Spain sought to identify baseline patterns of circulating microRNAs (which are small bits of noncoding ribonucleic acids that are involved in cell regulation) that were associated with positive blood pressure responses to continuous positive airway pressure in 24 men with resistant hypertension and obstructive sleep apnea; three of these microRNAs were identified in these patients. The researchers then tested whether these microRNAs predicted a positive response to continuous positive airway pressure in 14 similar patients (who comprised the validation group). The results confirmed that the same three microRNAs were predictive in the validation group, with very good discrimination. Plus, continuous positive airway pressure therapy was associated with changes in microRNA profiles, as well as with lower aldosterone-to-renin ratios in the responders. This study of resistant hypertension and obstructive sleep apnea is clearly exploratory, because of its small size and its inclusion of only men. Even so, it raises the hope that novel markers like microRNAs might be useful in predicting treatment response and optimizing decision making so-called personal or precision medicine ( http:// dx.doi.org /10.1016/ j. jacc.2015.07.014 ). As we await confirmation and further development of these findings, clinicians should remember that sleep apnea is becoming more prevalent, particularly as the population becomes more obese; left untreated, sleep apnea raises the risk for not only hypertension, but also cardiovascular diseases like heart failure. NEWS IN CONTEXT: ANTIDOTE TO DABIGATRAN IS APPROVED Dabigatran (trade name: Pradaxa) is an oral anticoagulant approved for treating patients who have atrial fibrillation or venous thromboembolism. The most important side effect of the drug is bleeding, but a specific antidote to reverse this anticoagulant has not been available. Until now. On October16, 2015 ( www. fda .gov /Drugs/InformationOnDrugs/ApprovedDrugs/ ucm467396.htm ), the Food and Drug Administration issued news of its approval of idarucizumab (trade name: Praxbind www. accessdata.fda .gov /drugsatfda_docs/label/2015/761025lbl.pdf ). Idarucizumab is a monoclonal antibody fragment that tightly binds to dabigatran and nullifies its anticoagulant activity. Approval was based on data from a randomized, placebo-controlled trial in healthy volunteers and a study of patients needing an urgent reversal because of bleeding or the need for a surgical procedure ( www.jwatch.org /NA38280 ). Plus, in an ongoing, open-label trial of patients with life-threatening or uncontrolled bleeding or who need emergency surgery or urgent procedures ( https://clinicaltrials .gov /ct2/show/NCT02104947 ), 90% of 120 patients exhibited a complete reversal of dabigatran within 4hours of getting idarucizumab. Currently, four new oral anticoagulant drugs are available in the United States: Three inhibit coagulation factor Xa, and one dabigatran is a thrombin inhibitor. Major bleeding with these drugs has generally been less common than with vitamin K antagonists like warfarin, but clinicians have to be able to rapidly reverse the anticoagulant activity of these drugs when theres dangerous bleeding or drug overdosing, or when patients need urgent surgery. Clinicians can now infuse idarucizumab to bind dabigatran, and an antidote (andexanet alfa) for the factor Xainhibiting drugs is currently in clinical trials ( https://clinicaltrials .gov /ct2/show/NCT02329327 ). POST-INFARCTION CARDIOMYOCYTE REGENERATION FACTOR FOUND IN MICE AND PIGS Human myocardium contains cardiac stem cells that can regenerate cardiomyocytes following the loss of these cells from myocardial infarction. But this regeneration isnt nearly robust enough to compensate for the cell loss caused by MI. So factors that could stimulate a more vigorous natural regeneration are needed. In a study in the September24 issue of Nature ( http:// dx.doi.org /10.1038/nature15372 ), researchers report that the epicardium which is the external epithelial layer of the heart plays an important role in the regeneration of myocardium following injury. Specifically, the researchers identified a molecule called FSTL1 thats produced by epicardial cells. FSTL1 is important in the embryonic development of the heart and continues to be produced in adulthood. But following infarction, the epicardium stops producing this molecule. The researchers triggered MIs in mice and surgically placed FSTL1 or placebo patches on the epicardial surface over the infarcted area. In mice that got FSTL1, cardiomyocytes were regenerated, vascularization increased, scarring was lessened, contractility improved, and lifespan was lengthened. Similar experiments on pigs (whose hearts are more like the human heart) produced comparable results. These researchers might have discovered a maladaptive response to myocardial infarction that prevents adequate cardiac regeneration and, possibly, a treatment that improves regeneration ( http:// dx.doi.org /10.1038/nature15217 ). Many more animal studies will be needed before the approach is tested in people. Developing ways to deliver FSTL1 to the epicardium in people with MI that dont involve surgically introduced patches will be challenging. ED VISITS RELATED TO DIETARYSUPPLEMENT USE OFTEN RESULT IN HOSPITALIZATION The Food and Drug Administration doesnt require the same level of safety testing for dietary supplements that it does for prescription and over-the-counter pharmaceuticals. So the safety of dietary supplements is relatively unknown, outside of those that have been recalled for serious adverse events, impurities, or the use of unapproved regulated substances. Using a nationally representative drug-event surveillance database (from 2004 to 2013), researchers analyzed all emergency department visits for adverse events associated with dietary supplements. Their findings appear in the October15 New England Journal of Medicine ( http:// dx.doi.org /10.1056/NEJMsa1504267 ). Based on nearly 3700 identified cases, the researchers estimated that 23,000 emergency department visits for adverse events related to dietary supplements happen every year in the United States and that 9% of them result in hospitalization. Children younger than 5 account for 20% of the visits, and young adults account for another 30%. The supplements that are implicated most often are those used for weight loss, energy, and sexual enhancement. The most commonly reported symptoms were cardiac (namely, palpitations, chest pain, or tachycardia) and neurological (namely, headache, dizziness, or presyncope). Among patients 65 or older, 40% of the visits were for supplement-induced swallowing problems, most likely due to large pill sizes. These findings should motivate clinicians to discuss supplement use and the potential for adverse events with patients, especially those with unexplained cardiac or neurological symptoms. NO CLINICAL BENEFIT FOR EARLYPHYSICAL THERAPY IN RECENT-ONSET LOW BACK PAIN The increasing use of imaging, opioids, and interventions (both percutaneous and surgical) in patients with low back pain is expensive and is not associated with better outcomes. Early physical therapy has been proposed to avoid these interventions, but clinical practice guidelines recommend against such use ( www.jwatch.org /jw200710250000001 ). In a study in the October13 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2015.11648 ), researchers randomized 220 adults with an average age of 37 and with recent-onset low back pain (lasting up to 2weeks), but without radicular symptoms below the knees, to either physical therapy or usual care. Physical therapy (started within 3days of enrollment) consisted of four sessions during 3weeks and emphasized spinal range-of-motion exercises, core strengthening, and home exercises. Both of the groups were encouraged to exercise and were educated about the favorable prognosis of low back pain. Adherence to physical therapy sessions in the intervention group was nearly 100%. Blinded evaluations of a variety of outcomes at 1 and 3months and again at a year were mixed, with several small statistically significant differences favoring the physical therapy group, but with no clinically important differences between the two groups. On the primary outcome (which was a 100-point standardized scale that evaluates pain, function, and disability), about a 4-point difference between the groups was recorded at a month. There was no difference between the groups in healthcare use; adverse effects in the physical therapy group were minimal. In many cases, its likely that primary care clinicians order early physical therapy just to offer patients something tangible, but this study suggests that most patients derive little if any clinical benefit from this intervention. Overall, these results support guidelines that recommend against early physical therapy. AVOID SEDATIVES AND OPIOIDS FOR LOW BACK PAIN Cyclobenzaprine (trade name: Flexeril) is a tricyclic antidepressant thats viewed as having muscle relaxant properties, even though it has no effect on motor neurons or skeletal muscle. Opioids act at the μ receptor to alleviate pain, but are also associated with addiction and death from overdose. The evidence for benefit of combining these agents with nonsteroidal anti-inflammatory therapy in patients with acute low back pain is limited, at best ( www.jwatch.org /jw200306270000002 and www.jwatch.org /em201002050000001 ). In a study in the October20 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2015.13043 ), researchers at a single academic emergency department randomized 320 patients with acute nontraumatic, nonradicular low back pain to 10-day courses of 500mg of naproxen twice /day plus 325 or 650mg of acetaminophen every 8hours, plus, one of three regimens: Namely, placebo, 5 or 10mg of cyclobenzaprine every 8hours, or 5 or 10mg of oxycodone every 8hours. After a week, all of the groups improved similarly as measured by a standard disability questionnaire. But a third of all of the patients still reported significant pain. Back pain is vexing for providers and patients alike. Opioids and so-called muscle relaxants add little to nonsteroidal anti-inflammatory medications. Cyclobenzaprine has sedative and anticholinergic side effects, and prescribing opioids for a condition that evidence-based guidelines warn against can lead to abuse and addiction. AGGRESSIVE TREATMENT vs . STANDARD CARE IN PATIENTS WITH PSORIATIC ARTHRITIS Although early and tight control of inflammation improves outcomes in patients with rheumatoid arthritis, this approach hasnt been studied for psoriatic arthritis. In a study on the website of The Lancet ( http:// dx.doi.org /10.1016/ S0140-6736(15)00347-5 ), researchers in the United Kingdom randomized 200 patients with early psoriatic arthritis (and no past treatment with disease-modifying antirheumatic drugs) either to tight control (with monthly evaluations and treatment adjusted according to a predefined protocol) or to standard care (with evaluations every 3months and no formal measures of disease activity). (The patients median age was 45 and the duration of symptoms was less than 2years.) The tight-control protocol entailed a rapid escalation of disease-modifying antirheumatic drug therapy (using methotrexate plus sulfasalazine, cyclosporine, or leflunomide) with the possible addition of tumor necrosis factor inhibitors. At a year, the likelihood of response (meaning at least a 20% improvement on an American College of Rheumatology assessment tool) was significantly higher in the tight-control group than in the standard-care group. But serious side effects were more common with tight control, and treatment was substantially more expensive. The radiographic progression of disease was similar in the two groups. This study shows that aggressive treatment is more effective than standard care in patients with psoriatic arthritis. But this finding comes with several caveats: The treatments used in the tight-control group (namely, methotrexate plus cyclosporine or leflunomide) are not always favored in the United States. Plus, tight control was more expensive and produced more serious adverse events than did standard care, and it didnt prevent the radiographic progression of disease. NO CLEAR BENEFIT OF EARLY NPPV IN IMMUNOCOMPROMISED PATIENTS WITH HYPOXEMIC RESPIRATORYFAILURE In a small trial conducted in the late 1990s, the early use of noninvasive positive-pressure ventilation conferred a mortality benefit in immunocompromised patients with hypoxemic respiratory failure ( www.jwatch.org /em200104180000001 ). Since then, outcomes in critically ill patients have improved dramatically, and more clinicians have begun to wonder whether early noninvasive positive-pressure ventilation is still warranted. In a multicenter trial on the website of JAMA ( http:// dx.doi.org /10.1001/jama.2015.12402 ), researchers in France randomized 370 immunocompromised patients in intensive care units to either noninvasive positive-pressure ventilation or oxygen therapy during the early stages of hypoxemic respiratory failure. The patients had hypoxemia, tachypnea, labored breathing, or respiratory distress; those with hypercarbia or an immediate need for intubation were excluded. Most of the patients were immunocompromised due to a malignancy or chemotherapy. At a month, all-cause mortality and the need for invasive ventilation were similar in the two groups. The researchers and editorialists emphasize ( http:// dx.doi.org /10.1001/jama.2015.12401 ) that the trial was underpowered to detect a mortality benefit and highlight the many risks associated with invasive ventilation these are considerations that suggest that clinicians should not abandon noninvasive positive-pressure ventilation. Even so, the findings of this trial might motivate clinicians to pause before starting noninvasive positive-pressure ventilation early in the course of hypoxemic respiratory failure in this population. In light of multiple recent studies ( www.jwatch.org /na37912 ), another interesting question is whether high-flow oxygen (used in only 40% of the study patients) might be of greater benefit than noninvasive positive-pressure ventilation in immunocompromised patients. This should be our next inquiry. GLIPTIN DRUGS, ADDED TO METFORMIN, MIGHT BENEFIT TYPE 2 DIABETICS In recent years, attention has been focused on the cardiovascular safety of diabetes drugs. In a population-based study on the website of the Annals of Internal Medicine ( http:// dx.doi.org /10.7326/M15-0308 ), researchers in Taiwan identified patients with type2 diabetes who had initially gotten metformin monotherapy, with the eventual addition of either a sulfonylurea or a dipeptidyl peptidase-4 inhibitor (like sitagliptin [trade name: Januvia] and saxagliptin [trade name: Onglyza]). About 10,000 sulfonylurea patients and 10,000 gliptin patients, closely matched through propensity scoring, were compared. During an average follow-up of about 3years, the dipeptidyl peptidase-4 inhibitor group, compared with the sulfonylurea group, had significantly lower incidences of death and stroke, but not myocardial infarction or heart failurerelated hospitalization. In this observational study, add-on dipeptidyl peptidase-4 inhibitor therapy was associated with favorable outcomes compared with add-on sulfonylurea therapy, but residual confounding could have still been a factor. Proponents of the gliptin drugs will likely cite this study as showing that these drugs might prevent stroke and even death. But that interpretation would be misleading, because the researchers included no comparison group with continued metformin monotherapy. In fact, in recently published trials ( www.jwatch.org /na38165 and www.jwatch.org /na32162 ), neither sitagliptin nor saxagliptin lowered the incidence of myocardial infarction, stroke, or death compared with placebo, and most of the patients in those studies were also on background therapy with metformin. COULD A DIABETES DRUG CURE CML? Chronic myelogenous leukemia is caused by a chromosomal translocation that creates a fused gene; this gene produces an oncoprotein called BCR-ABL. Targeting this protein with imatinib (trade name: Gleevec) and other tyrosine kinase inhibitors produces dramatic clinical improvement in many patients but produces few cures. Its believed that cures are prevented because dormant (meaning, nonreplicating) cancer stem cells are not killed by tyrosine kinase inhibitors and thereby sustain disease. In a study in the September17 issue of Nature ( http:// dx.doi.org /10.1038/nature15248 ), researchers in France report that a molecular pathway, triggered by the activation of peroxisome proliferator-activated receptor gamma, causes fewer cancer stem cells to stay dormant, thereby rendering them more vulnerable to treatment. The researchers added the PPARγ-activating drug pioglitazone (which is approved to treat diabetes) to imatinib in three patients with chronic myeloid leukemia who had responded to imatinib, but who hadnt achieved complete molecular responses (namely the eradication of BCR-ABL transcripts). Each patient had a complete molecular response that has lasted as long as nearly 5years. In an ongoing nonrandomized phase II trial ( https:// www. clinicaltrialsregister.eu/ctr-search/trial/ 2009-011675-79 /FR ), researchers report preliminary results showing that 60% of patients have achieved complete molecular responses so far. These researchers might have identified a drug (pioglitazone) approved by the Food and Drug Administration that, when added to tyrosine kinase inhibitors, improves clinical response and promotes durable complete molecular responses in patients with chronic myeloid leukemia. This result also supports the theory that cancer stem cells perpetuate cancer ( http:// dx.doi.org /10.1038/nature15213 ). Whether the promise of this study will be realized in large randomized trials, and whether it will apply to other malignancies treated by tyrosine kinase inhibitors, remains to be seen. TWO-YEAR TRIAL SUPPORTS CARDIOMETABOLIC BENEFITS OF MODERATE WINE CONSUMPTION Its been shown that moderate alcohol drinkers have lower incidences of type2 diabetes and cardiovascular disease than do nondrinkers or heavy drinkers. The results have been mixed on whether red wine has special benefits over other alcoholic beverages. In an international trial in the October20 Annals of Internal Medicine ( http:// dx.doi.org /10.7326/M14-1650 ), researchers studied 220 patients in Israel between the ages of 40 and 75 with type2 diabetes who regularly drank no more than one alcoholic drink /week at baseline. The patients all ate a Mediterranean diet, without caloric restriction, and were randomized to drink 150mL of red wine, white wine, or mineral water each evening. Adherence was excellent. At 2years, compared with the water drinkers, the red wine drinkers had higher HDL cholesterol levels (by 2 mg/ dL), lower total/HDL cholesterol ratios, and fewer markers for metabolic syndrome; the white wine drinkers had lower fasting blood glucose and triglyceride levels and less insulin resistance. There were no differences among the groups in blood pressure, adiposity, liver function, drug therapy, symptoms, or quality of life (except that the wine drinkers reported sleeping better). This 2-year controlled trial in patients with type2 diabetes suggests that red wine has modest benefits for raising HDL cholesterol levels and preventing metabolic syndrome, whereas white wine might modestly improve carbohydrate metabolism. The study was not designed to evaluate clinical outcomes or the incidence of new-onset type2 diabetes, and its results might not apply to patients who dont already have diabetes. EFFECTS OF ALCOHOL CONSUMPTION DIFFER BETWEEN RICH AND POORCOUNTRIES Alcohol consumption is the third most-important modifiable risk factor for disability and death worldwide, but its association with health is complex. Moderate intake might lower the risk for myocardial infarction, whereas the risk for some cancers rises with total intake over time, and heavy episodic intake is associated with an excess risk for trauma and sudden cardiac death. Although patterns of alcohol use vary regionally, most of the data on alcohol and health have come from upper-income countries. In a prospective cohort study on the website of The Lancet ( http:// dx.doi.org /10.1016/ S0140-6736(15)00235-4 ), researchers analyzed data from nearly 115,000 patients between the ages of 35 and 70 in 12 countries that varied considerably in average income. The patients were asked at baseline about their quantity, pattern, and type of alcohol consumed; they were categorized as never, former, or current drinkers and were followed for a median of 4years. Compared with the never drinkers, the current drinkers had a lower risk for MI and hospitalization, a higher risk for incident cancer (mainly among older drinkers), and a higher risk for injury (mainly among younger, episodic drinkers); current and never drinkers had similar risks for cardiovascular disease, stroke, or death. Among the current drinkers, the risk for a composite of all of these outcomes was lower in high-income and upper-middle-income countries (where a moderate intake of wine is common), but the risk was higher in lower-middle-income and low-income countries (where binge drinking of liquor is more prevalent). Although these researchers examined only country-level associations, their findings on the effects of alcohol consumption raise interesting questions about variations within wealthy countries, like the United States, where differences in drinking patterns in rich and poor communities might be associated with different health outcomes. ADDING DIETARY CALCIUM OR CALCIUM SUPPLEMENTS RESULTS IN ONLY SMALL INCREASES IN BMD Often, clinicians tell their patients to increase their dietary calcium intake and prescribe calcium supplements to prevent and manage osteoporosis. In a meta-analysis on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. h4183 ), researchers reviewed 60 randomized controlled trials to see whether raising dietary calcium intake (data from 1500 patients) and taking calcium supplements (data from 12,000 patients) increases bone-mineral density. The patients (nearly all women 50 or older at baseline) had undergone baseline and postintervention bone-mineral density testing. Increasing dietary calcium intake (to between 250 and 3300 mg/ day) significantly increased baseline bone-mineral density by 0.6% to 1% at the total hip and total body at a year and by 0.7% to 1.8% at the total hip, total body, femoral neck, and lumbar spine at 2years; there were no changes at the forearm. Calcium supplements (250 to 2500 mg/ day) increased bone-mineral density by 0.7% to 1.4% at all five sites at a year with little change after that. Overall, increases in bone-mineral density were similar in all of the analyzed trial groups, namely, augmented dietary calcium vs . calcium supplements (except at the forearm), calcium monotherapy vs . calcium plus vitamin D, calcium doses of 1000 mg/ day or greater vs . doses of less than 1000mg, and a baseline dietary calcium intake of 800 mg/ day or greater vs . an intake of less than 800mg. The results of this meta-analysis show that augmenting dietary calcium intake or taking calcium supplements results in small increases in bone-mineral density during 1 to 2years. Because bone-mineral density is only a surrogate marker for fracture risk, such small increases in bone-mineral density are unlikely to translate into clinically meaningful reductions in the incidence of fractures; in fact, in a companion meta-analysis, these authors found little evidence that dietary or supplemental calcium prevents fractures ( www.jwatch.org /NA39414 ). Clinicians should not recommend an increased intake of calcium to all patients simply to increase bone-mineral density. Instead, recommending a diet that meets recommended daily intakes for calcium and vitamin D and exercise programs and other measures that prevent falls is a sensible approach. CALCIUM SUPPLEMENTS PROBABLY WONT AFFECT FRACTURE RISK IN MOST OLDER ADULTS Experts recommend that elders take in at least 1000 to 1200 mg/ day of calcium to prevent fractures, and many older patients take calcium supplements to meet this recommendation. In a systematic review in The BMJ ( http:// dx.doi.org /10.1136/bm j. h4580 ), researchers examined the evidence from randomized, controlled trials and observational studies to determine the effects of dietary calcium and calcium supplements on fracture risk in patients older than 50. The researchers analyzed 60 cohort studies of dietary calcium, milk, or dairy intake and fracture risk in more than 700,000 patients. Three quarters of the studies reported no association between dietary calcium intake and the risk for total fracture, hip fracture, vertebral fracture, or forearm fracture; positive associations in the rest of the studies were weak. Similarly, neither milk intake nor dairy intake was associated with a risk for fracture. In analyses of data from 30 randomized trials (with 70,000mostly female patients) in which the effects of calcium supplements (1000 mg/ day or more) on fracture risk were evaluated, calcium supplements lowered the risks for total fracture and for vertebral fracture, but not for hip or forearm fracture. Its important to mention that there was evidence of publication bias in some of the trials. This systematic review shows that dietary calcium, milk, and dairy intakes are not associated with the risk for fracture and that calcium supplements have minimal effects, at best, on fracture risk. As the researchers contend, widespread untargeted use of calcium supplements in older patients is unlikely to result in a lower incidence of fractures. Notably, calcium supplements have been associated with harms, including adverse cardiovascular events ( www.jwatch.org /jw201105120000001 ) and gastrointestinal symptoms. IS A STRUCTURED REHABILITATION PROGRAM USEFUL AFTER ANKLEFRACTURE? Treating patients with ankle fractures, whether by open or closed reduction, always requires immobilization, and the recovery from that immobilization can be slow or incomplete. In a study in the October6 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2015.12180 ), researchers in Australia randomized 214 adults with ankle fractures (and an average age of 41) to either a structured exercise program or usual advice following immobilization; the average duration of immobilization was almost 7weeks, and about half of the patients underwent open reduction and internal fixation. The exercise program was supervised by physical therapists (1 to 2 times /week for a month) and emphasized ankle mobility, strength, and balance. Usual advice consisted of general encouragement to walk as tolerated with ankle dorsiflexion and plantar flexion on a step. In blinded evaluations at 1, 3, and 6months, there were no significant differences in the improvement of function or in average overall quality of life between the two groups. None of 17 secondary outcomes showed between-group differences; fracture severity, age, and the sex of the patients didnt influence outcomes. Usually, routine educational advice is enough for patients following immobilization for ankle fractures. But this study does not address the more important, although less common, situation of when and how to prescribe a structured physical therapy program for the patients with ankle fractures or sprains who dont recover function after usual self-management advice. OLD-FASHIONED SURGERY FOR PERFORATED DIVERTICULITIS STILL ISBETTER Its been suggested that the outcomes of surgery for perforated acute diverticulitis are better with laparoscopic peritoneal lavage than with traditional colon resection with or without diversion. But recently, a randomized trial of the two techniques was stopped early because of excess adverse events with laparoscopic lavage ( http:// dx.doi.org /10.1016/ S0140-6736(15)61168-0 ). To compare these two surgical approaches further, researchers in Sweden and Norway randomized 200 patients who presented with diverticulitis showing free air on abdominal computed tomography scans to either laparoscopic lavage or primary resection. Findings appear in the October6 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2015.12076 ). The rates of severe postoperative complications (which was the primary outcome) were similar in the two groups (at around 30%) as were mortality at 3months, length of hospital stay, and quality of life. The rates of reoperation were higher in the lavage group (in which four patients needed reoperation for missed sigmoid cancers) than in the resection group. Two randomized, controlled trials of laparoscopic peritoneal lavage vs . primary resection for acute perforated diverticulitis have now shown that resection is better. PERFORM CHOLECYSTECTOMY DURING INITIAL HOSPITALIZATION FOR GALLSTONE PANCREATITIS Despite recommendations that advocate for cholecystectomy during the index hospital admission for mild gallstone pancreatitis, most patients in the United States undergo cholecystectomy several weeks after discharge. To evaluate the effect of the timing of cholecystectomy in patients with mild gallstone pancreatitis, researchers in the Netherlands randomized 270 patients to undergo cholecystectomy during the same hospital admission or electively several weeks later (this was the interval group). Cholecystectomy was performed at a median of 1day after randomization in the same-admission group and 27days after randomization in the interval group. Details appear in the September26 issue of The Lancet ( http:// dx.doi.org /10.1016/ S0140-6736(15)00274-3 ). The combined endpoint of mortality or gallstone-related complications (namely, recurrent pancreatitis, cholangitis, cholecystitis, choledocholithiasis that required endoscopic retrograde cholangiopancreatography, or biliary colic) was seen significantly less often in the same-admission group than in the interval group. There was no difference in surgical complications in the two groups. These findings show that the common practice of delaying cholecystectomy leads to higher rates of preventable, recurrent, stone-related complications than does a strategy of cholecystectomy during the index hospitalization. Although surgeons might express concern about operating in the setting of pancreatitis, these results did not show an excess of surgical complications. In patients with mild gallstone pancreatitis who are otherwise fit for surgery, cholecystectomy should be performed before discharge thats a major change from current practice.

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Learning Format 6 Hours
Self-Study

Credit Type(s)
Cardiology Rheumatology Internal Medicine