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. Jessica Mega reported receiving grant support awarded to Brigham and Womens Hospital from AstraZeneca, Bayer, BMS, Daiichi Sankyo, Eli Lilly, Janssen, and Sanofi and receiving consulting fees from American Genomics, AstraZeneca, Bayer, Janssen, and Portola. She is currently working with Google X. Dr. Anthony DeMaria and the planning committee members reported that they had nothing to disclose. EFFICACY OF 13-VALENT PNEUMOCOCCAL CONJUGATE VACCINEIN OLDER ADULTS The 13-valent pneumococcal conjugate vaccine (trade name: Prevnar 13) was first recommended for use in patients 65 or older ( www.jwatch.org /NA36917 ) on the basis of the preliminary results from a giant industry-sponsored trial. The final results from this study have now been published in the March19 New England Journal of Medicine ( http:// dx.doi.org /10.1056/NEJMoa1408544 ). Almost 90,000 patients in the Netherlands with an average age of 73 were randomized to either the 13-valent pneumococcal conjugate vaccine or placebo. None of the patients had gotten the 23-valent pneumococcal vaccine in the past, and about 90% of both of the groups got annual influenza vaccinations. During a median follow-up of 4years, the vaccine offered significant protection against invasive pneumococcal disease (the vaccine was 75% effective against disease caused by vaccine-type strains and about 50% effective overall). It was also about 45% effective against vaccine-type uncomplicated nonbacteremic pneumonia. Protection lasted for the duration of the trial. The vaccine didnt protect against all-cause community-acquired pneumonia, and it didnt affect mortality. There were no serious side effects. Policy-setting organizations now endorse the use of the 13-valent pneumococcal conjugate vaccine in older patients, as well as in all adults who have immunocompromising conditions that might increase therisk for pneumococcal disease. Despite the vaccines clear efficacy, there are still some practical matters to be worked out, including a schedule for boosters and the best way to combine this vaccine with the 23-valent vaccine (whose use is still endorsed in older patients because of its broader spectrum of protection). The current recommendations from the Centers for Disease Control and Prevention for deploying the two pneumococcal vaccines in combination are available online ( www. cdc .gov /mmwr/preview/mmwrhtml/mm6337a4.htm ). COMPARING ANTIBIOTIC TREATMENTOPTIONS FOR CAP Guidelines recommend either fluoroquinolone monotherapy or combination therapy with a β-lactam plus a macrolide or fluoroquinolone as empirical treatment for patients with suspected community-acquired pneumonia who need hospitalization, but not admission into an intensive care unit. Unfortunately, the data supporting these recommendations arent robust. Now, in a randomized crossover trial in the April2 New England Journal of Medicine ( http:// dx.doi.org /10.1056/NEJMoa1406330 ), researchers in the Netherlands compared β-lactam monotherapy, fluoroquinolone monotherapy, and β-lactammacrolide combination therapy in more than 2000 adults with suspected community-acquired pneumonia who were hospitalized on non-ICU wards at seven hospitals. Microbial etiology was determined in only a minority of the patients: The most common pathogens were Streptococcus pneumoniae and Haemophilus influenzae ; atypical pathogens were found in only 2% of the cases. Noninferiority analyses showed no significant difference in 3-month mortality for the three regimens in the intent-to-treat or antibiotic-adherent populations. There were no clinically relevant differences among the groups in hospital lengths of stay or in the rates of major or minor complications. The shift from intravenous to oral antibiotic therapy happened earlier with fluoroquinolone monotherapy than with either of the other regimens. As the researchers acknowledge, the number of trial participants with Legionella pneumophila or other atypical pathogens was extremely low. Still, this real-world study suggests that, for many non-intensive care unit patients with suspected community-acquired pneumonia, broader-spectrum antibiotics arent warranted. With todays concerns regarding increasing resistance to fluoroquinolones and macrolides as well as antibiotic overuse, clinicians can rightly question the appropriateness of hospital quality measures based on the adherence to current guideline-recommended antibiotic regimens for patients with community-acquired pneumonia. DISCUSSING A PATIENTS PROGNOSIS WITH SURROGATES IN THE ICU Often, caring for patients who are critically ill includes discussions with the patients surrogates about prognosis and the goals of care. Although expert guidelines exist on how best to communicate prognosis, we dont really have any evaluations of best practices. Until now. Two studies (with some shared researchers) shed light on this process. The patients in these studies were adults with acute respiratory distress syndrome at five medical centers in the United States. In the first study, the results of which appear in the February Annals of the American Thoracic Society ( http:// dx.doi.org /10.1513/AnnalsATS.201407-325OC ), researchers analyzed interviews to identify the characteristics of effective communication about prognoses. The 118 participants included surrogates, doctors, nurses, social workers, chaplains, and communication experts. Many themes that emerged were consistent with those in current guidelines about communication, including truthful disclosure, so-called teach-back strategies, emotional support, and tailoring disclosure strategies to the needs of the surrogates. Additional concepts that arose were using visual illustrations (like x-rays or drawings on whiteboards) to increase understanding, alerting families early after patients hospital admissions that death was a possible outcome, and iterative discussions of prognosis with the engagement of multiple disciplines. Although concordance was strong between the participant groups, there were marked differences in the groups perceptions of the value of numeric prognostication: Only 12% of the doctors felt that giving numeric estimates of survival was appropriate, whereas most of the other participants supported this practice. Interestingly, eliciting family perspective and understanding before giving information is central to many guidelines and is supported by clinicians, but only 9% of the surrogates themselves identified this factor as being important. In the second study, the results of which appear in the Marchissue of Critical Care Medicine ( http:// dx.doi.org /10.1097/CCM.0000000000000719 ), researchers sought to understand whether surrogates perception of the quality of communication correlated with an accurate understanding of prognosis. The participants were from urban academic medical centers, and most were white and spoke English. Data from 260 physiciansurrogate paired questionnaires showed that surrogates rated their communications with clinicians (namely, doctors bedside manners and communication about prognosis) as high quality. Unfortunately, in multiple analyses, perceived quality of communication had no predictive value in determining concordance between doctors and surrogates understanding of prognoses. Most commonly, the surrogates were more optimistic than were the doctors. Although these studies were done in intensive care units, this problem isnt exclusive to that setting. These studies highlight the challenges of communicating about prognosis, but also suggest additional strategies that might help increase effectiveness. The lack of concordance between the quality of communication and understanding about prognosis is somewhat disheartening, but maybe not surprising. Clinicians can run a great family meeting, but the family still might not be there yet. Just hearing the prognosis from a doctor isnt enough; the entire multidisciplinary team needs to collaborate in helping the family understand the severity of illness. Often, informal bedside discussions with nurses move this process along, beyond the formal family meeting. Discussions should be started early and continued iteratively, and clinicians should ensure that various providers are reasonably aligned in how they communicate medical course and prognosis to minimize misunderstanding and confusion. During this process, providers have to be attuned to family dynamics and the psychosocial background that makes each case unique. Finally, using numerical prognostic estimates warrants greater study. Although clinicians are disinclined to give numbers for many good reasons, surrogates understanding might be better if estimates were included more often. PHARMACOGENETIC TESTING IDENTIFIES PATIENTS AT HIGHEST BLEEDING RISK FROM WARFARIN Polymorphisms in two genes, CYP2C9 and VKORC1 , account for about 40% of the variability in patients responses to warfarin. Initial-dosing recommendations, approved by the Food and Drug Administration, are based on these genetic parameters. The dosing recommendations increase the time in the therapeutic range, but because genotype-based dosing hasnt been shown to improve clinical outcomes, these genetic tests arent reimbursed by Medicare. New oral anticoagulants, like the recently licensed factor Xa inhibitor edoxaban (trade name: Savaysa), are as effective as warfarin, with more predictable pharmacodynamics and a lower risk for bleeding. In a trial from last year ( www.jwatch.org /na32803 ), researchers randomized more than 20,000 patients with nonvalvular atrial fibrillation either to warfarin (titrated to an international normalized ratio of 2 to 3) or to 30 or 60 mg/ day of edoxaban for a median of 3years. In a study on the website of The Lancet ( http:// dx.doi.org /10.1016/ S0140- 6736(14)61994-2 ), researchers grouped more than 14,000 of these patients genotyped for variants in CYP2CP and VKORC1 as normal, sensitive, or highly sensitive warfarin responders. In the first 3months of treatment, the sensitive and the highly sensitive responders spent a greater proportion of time overanticoagulated than did the normal responders, and they were at an excess risk for bleeding complications. In the sensitive and the highly sensitive responders, the risk for bleeding was reduced more in those who took edoxaban (compared with warfarin) than it was in the normal responders. After 3months, the difference in bleeding risk between edoxaban and warfarin was similar in all of the genotype groups. An editorialist suggests ( http:// dx.doi.org /10.1016/ S0140- 6736(14)62219-4 ) that patients at the highest genetic risk for warfarin-related bleeding complications would derive the greatest benefit from the safer, but more expensive, new oral anticoagulants; he urges the Centers for Medicare and Medicaid Services to reconsider their payment policy for these genetic tests. ORAL ANTICOAGULANT-RELATED HEMORRHAGE: IMPROVING MANAGEMENT OF A RISKY CONDITION Intracerebral hemorrhage can be a devastating complication of oral anticoagulant use. Using data from 19 tertiary care centers involving 1200 patients with oral anticoagulant-related intracerebral hemorrhage and an average age of 74, researchers in Germany examined the factors associated with hematoma enlargement and outcomes after the resumption of therapy with oral anticoagulants. Their findings appear in the February24 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2015.0846 ). Two factors were associated with significantly lower odds of hematoma enlargement, namely, the reversal of anticoagulation within 4hours and a systolic blood pressure of 160mmHg or lower at 4hours. Hematoma enlargement was seen in 20% of the patients with an international normalized ratio lower than 1.3 vs . 40% of the patients with an INR of 1.3 or higher. Hematoma enlargement was also seen in a third of the patients with a systolic blood pressure of 160mmHg or lower vs . half of the patients with a higher systolic pressure. The patients who achieved both metrics had significantly lower in-hospital mortality. More than 700 patients survived. The 170 survivors who resumed oral anticoagulants had significantly fewer ischemic complications than those who didnt resume therapy with oral anticoagulants. Hemorrhagic complications were similar (at about 8%) in the two groups. This study provides clinical management goals for patients with oral anticoagulant-related intracerebral hemorrhage. An aggressive reversal of anticoagulation and systolic blood pressure lowering to 160mmHg or lower were associated with fewer hematoma enlargements and lower in-hospital mortality. Survivors in reasonable clinical condition should be considered for oral anticoagulant resumption; the novel oral anticoagulants are attractive for this population due to these agents substantially lower risk for intracerebral hemorrhage. Because these data are retrospective, we need prospective validation. IS LOW BP HARMFUL IN PATIENTS WITH DEMENTIA OR COGNITIVEIMPAIRMENT? Hypertension and cognitive impairment commonly coexist, but the associations among hypertension, hypertension treatment, and cognitive decline arent clear. In a prospective cohort study in the Aprilissue of JAMA Internal Medicine ( http:// dx.doi.org /10.1001/jamainternmed.2014.8164 ), researchers in Italy performed baseline evaluations of 170 patients with an average age of 79 (two thirds had dementia and the rest had mild cognitive impairment); they checked the presence of cardiovascular and other chronic diseases, antihypertensive medication use, office blood pressure, cognitive function (based on the Mini-Mental State Exam score, which ranges from 0 to 30), and daily living function. The patients also underwent ambulatory blood pressure monitoring. The average exam score at baseline was 22; 70% of the patients were taking antihypertensive medications. The patients were stratified into three groups, based on average daytime ambulatory systolic blood pressure (namely, up to 128mmHg, between 129 and 144mmHg, and 145mmHg or higher). During a median follow-up of 9months, there was a significantly greater decline in average cognitive function scores in the patients with the lowest systolic blood pressures. When the patients were stratified by antihypertensive drug use, the association was significant only among those taking antihypertensives. The results were similar in analyses adjusted for demographic and vascular disease factors. The results were also similar for office-measured systolic blood pressure, but the association was weaker and didnt reach statistical significance. Despite the medical complexity of these patients and the limitations of a cohort study, these results suggest that an overly aggressive treatment of hypertension in older patients with dementia or cognitive impairment is harmful; clearly, we need clinical trials. At a minimum, intermittent ambulatory blood pressure monitoring might be needed to overcome the known inaccuracies of measuring blood pressure during an office visit. REAL-WORLD OUTCOMES WITH CAROTID REVASCULARIZATION Carotid revascularization is worthwhile only when perioperative morbidity and mortality are low and when patients are destined to live long enough to accrue benefit. But two studies raise questions about patient selection for this procedure. In the first study, the results of which appear in the Marchissue of JAMA Neurology ( http:// dx.doi.org /10.1001/jamaneurol.2014.3638 ), researchers collected data on perioperative and longer-term outcomes for more than 20,000 Medicare patients with an average age of 76 who underwent carotid stenting between 2005 and 2009. The burden of comorbidities was high, and carotid stenosis was asymptomatic in about half of the patients. The outcomes for patients with asymptomatic stenosis were: At 30days, the rate of death was 1%, and the rates of stroke or transient ischemic attack and myocardial infarction were both about 2%. At 2-years, the rate of death was nearly 30% and the rate of stroke or transient ischemic attack was 7%. The outcomes for patients with symptomatic stenosis were: At 30days, the rate of death was 2%, the rate of stroke ortransient ischemic attack was 4%, and the rate of MI was 3%. At 2years, the rate of death was nearly 40% and the rate of stroke or transient ischemic attack was 12%. In the second study, the results of which appear in the March Journal of Vascular Surgery ( http:// dx.doi.org /10.1016/ j. jvs.2014.10.002 ), researchers identified more than 2000 dialysis patients from a renal database who underwent carotid revascularization (mostly endarterectomy) for asymptomatic stenosis between 2005 and 2008. Thirty-day mortality was 5%, and the 30-day stroke rate was 6%. At a year, a third of the patients had died or had experienced strokes. In these studies, perioperative morbidity and mortality were substantial, and large proportions of the patients many of whom were older and frail died within 2years. Plus, in the Medicare study, most of the patients were treated by doctors who didnt meet the levels of proficiency that had been required in clinical trials of stenting. Although medically treated control groups werent available for comparison in these studies, the findings suggest that carotid revascularization is being performed in many patients for whom the short-term harms likely outweigh any potential long-term benefit. STENTING FOR SYMPTOMATIC INTRACRANIAL ATHEROSCLEROSIS LEADS TO HARM Because large-artery atherosclerosis is a high-risk cause of stroke, stent technologies have been developed to treat patients with severely stenotic intracranial atherosclerotic lesions. In the first reported randomized trial of such treatment back in 2011 (known by the acronym SAMMPRIS), the risk for stroke or death was higher with stenting than with medical therapy alone ( www.jwatch.org /jw201109290000005 ). After the SAMMPRIS results were released, enrollment was stopped in the so-called VISSIT trial, and its findings were published in the March24 and 31 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2015.1693 ). VISSIT was a multicenter randomized trial in which medical therapy alone was compared with balloon-expandable stents in patients who had recent stroke or transient ischemic attack in the territory of a 70 to 99% intracranial arterial stenosis. Medical therapy in both of the groups involved antiplatelet drugs, statins, and a systolic blood pressure goal of no higher than 140mmHg. Among 112 patients enrolled before recruitment was stopped, there were significantly more recurrent strokes and transient ischemic attacks after stenting than with medical therapy alone. The rates of this primary outcome continued to diverge between the two groups after the 30-day periprocedural period, indicating that even successful stenting didnt lower the long-term risk for stroke. The results of SAMMPRIS and VISSIT show that intracranial stenting of atherosclerotic lesions leads to substantial harm. Patients at the highest risk for recurrent stroke are also at the highest risk for stenting complications, making any potential benefit from stenting unlikely. Even successful stent implantation without periprocedural complications doesnt provide long-term benefit. ACCURACY OF THE ACC/AHA CVCALCULATOR IS CHALLENGED Since the 2013 release of the American College of Cardiology and the American Heart Association 10-year cardiovascular risk calculator ( www.jwatch.org /NA32830 ), several analyses have challenged its accuracy ( http:// dx.doi.org /10.1016/ S0140- 6736(13)62388-0 and http:// dx.doi.org /10.1001/jamainternmed.2014.5336 ). Because the calculator is used to select patients for statin therapy, the implications of inaccuracy are important. In an analysis in the February17 Annals of Internal Medicine ( http:// dx.doi.org /10.7326/M14-1281 ), researchers used data from the MESA study which was a contemporary, multiethnic, prospective epidemiologic study to examine the accuracy of five risk-score calculators, including the American College of Cardiology and the American Heart Association calculator. The cohort included more than 4000 patients between the ages of 50 and 74 without clinical cardiovascular disease or diabetes at baseline; average follow-up was 10years. The Reynolds risk score performed relatively accurately in the MESA population. In contrast, three Framingham-based risk scoring systems and the American College of Cardiology and the American Heart Association calculator substantially overestimated risk. The American College of Cardiology and the American Heart Association scores predicted an event rate of 9%, but the actual observed rate was only 5%, so the risk was overestimated by about 80%. In the MESA patients whose American College of Cardiology and American Heart Association-predicted 10-year risk was between 7.5% and 10% (which is the threshold at which those organizations recommend statin therapy), the actual observed event rate was only 3% in men and 5% in women. This study (in conjunction with its predecessors that reached similar conclusions) poses a serious problem for the American College of Cardiology and the American Heart Association calculator. Some commentators have glossed over the issue of overestimated risk, implying that some overtreatment with statins isnt important. But that reaction isnt valid. The rationale for risk prediction is precisely to distinguish between the patients who are reasonably likely to benefit from drug therapy and the patients whose probability of benefit is marginal or absent. ANOTHER RANDOMIZED TRIAL OF CTCA TO EVALUATE CHEST PAIN The SCOT-HEART trial is one of two new studies designed to examine the role of computed tomographic coronary angiography in evaluating patients with suspected coronary heart disease. Its findings appear on the website of The Lancet ( http:// dx.doi.org /10.1016/ S0140- 6736(15)60291-4 ). The trial involved more than 4000 patients in Scotland with stable chest pain who were referred by primary care clinicians to dedicated cardiology chest pain clinics. During the initial evaluation, nearly all of the patients underwent exercise stress testing (without imaging). Plus, researchers randomized all of the patients either to undergo CT coronary angiography (within 2weeks) or to no CT coronary angiography. Clinicians were permitted to order stress imaging tests regardless of the randomized group; these were scheduled for a third of the patients in each group. The primary endpoint was certainty of the diagnosis of angina secondary to coronary heart disease at 6weeks: Diagnoses were considered to be certain (that is to say, yes or no, as opposed to probable or unlikely) in a third of the CT coronary angiography patients and in 20% of the controls thats a significant difference. The CT coronary angiography patients were much more likely than were the controls to have previously scheduled stress imaging canceled or to have invasive coronary angiography scheduled for the first time. During an average follow-up of about 1.7years, the two groups were similar in clinical outcomes, although there were several nonsignificant trends (for example, the CT coronary angiography group, compared with the controls, had fewer nonfatal myocardial infarctions and more coronary revascularization procedures). These results are difficult to interpret. It seems obvious that computed tomographic coronary angiography would increase diagnostic certainty (which was the studys primary outcome): The presence or absence of obstructive lesions will undoubtedly influence a clinicians perception of whether chest pain represents coronary ischemia. Plus, the liberal use of additional stress imaging in both the CT coronary angiography and no-CT coronary angiography groups muddles the picture of what tests (or combination thereof) guided subsequent management decisions. In the other recent trial, called PROMISE ( www.jwatch.org /na37279 ), patients were randomized either to CT coronary angiography or stress testing (usually with nuclear or echocardiographic imaging), and clinical outcomes in the two groups were also similar. Interestingly, CT coronary angiography increased the rates of subsequent invasive angiography and revascularization by several percentage points in both of these trials, but it didnt clearly improve clinical outcomes during an average follow-up of about 2years. DO Gliptin DRUGS RAISE RISK FOR HEART FAILURE? The Food and Drug Administration requires evidence that new therapies for type2 diabetes dont raise cardiovascular risk. Two years ago, in placebo-controlled trials of dipeptidyl peptidase4 inhibitors, saxagliptin (trade name: Onglyza) was evaluated in 17,000 patients with diabetes and cardiovascular disease or risk factors, and alogliptin (trade name: Nesina) was evaluated in 5000 patients with diabetes and recent episodes of acute coronary syndrome ( www.jwatch.org /na32162 ). In the saxagliptin study, major adverse cardiovascular events (like cardiovascular death, myocardial infarction, and stroke) were seen with similar frequency during 2years in both the saxagliptin and the placebo groups, but the incidence of hospitalizations for congestive heart failure was significantly higher in the saxagliptin group. In the alogliptin study, the incidence of major cardiovascular events was also similar in the treatment and placebo groups, but congestive heart failure hospitalizations werent examined. Now, on the website of The Lancet ( http:// dx.doi.org /10.1016/ S0140- 6736(14)62225-X ), the researchers of the alogliptin study have analyzed congestive heart failure-related outcomes. Major adverse cardiovascular events were more common in the patients with preexisting congestive heart failure than in those without it, but, among all of the patients, the risk was similar in the alogliptin and placebo groups. Composite outcomes that included congestive heart failure hospitalization were also similar in the two groups, regardless of the history of congestive heart failure. But among the patients without preexisting congestive heart failure, those taking alogliptin were significantly more likely to have a first hospitalization for congestive heartfailure. The smaller study of alogliptin might have lacked statistical power to discern differences in congestive heart failure outcomes that emerged in the larger study of saxagliptin, and the durations of both of the studies were relatively brief. Dipeptidyl peptidase4 inhibitors seem to have little effect on cardiovascular-related death, myocardial infarction, or stroke, but their effects on congestive heart failure require further clarification ( http:// dx.doi.org /10.1016/ S0140- 6736(15)60037-X ). TREATING PATIENTS WITH DIABETICFOOT OSTEOMYELITIS Usually, when osteomyelitis complicates diabetic foot infections, amputation or aggressive surgical debridement is recommended. When neither of these options is possible, prolonged antibiotic courses are substituted. Unfortunately, no one knows exactly how long a course islong enough. In a study in the Februaryissue of Diabetes Care ( http://care.diabetesjournals .org /content/38/2/302 ), researchers in France randomized 40 diabetic adults with biopsy-confirmed osteomyelitis of the foot to treatment with either 6 or 12weeks of antibiotics alone, without surgery. Most of the patients had infection of one of the metatarsal heads. The selection of antibiotic was dictated by the culture results of the biopsy specimens, and antibiotics were administered orally for all but the first few days of treatment. No patient had evidence of vascular disease, none had gangrene, and those for whom surgical intervention was clearly mandated because of bone or joint destruction were excluded. A year after completing treatment, 12 patients in the 6-week group and 14 patients in the 12-week group were considered to be cured this difference wasnt significant. No clinical or microbiological parameters were identified that might have predicted treatment failure among the remaining patients. Not surprisingly, antibiotic side effects, mostly gastrointestinal, were more common in the 12-week group. This study suggests that, in a very carefully selected subset of patients with diabetic foot osteomyelitis, 6weeks of precisely chosen antibiotics might cure without the need for surgery, and that longer courses of antibiotic therapy wont improve cure rates. But patients with feet healthy enough to qualify for this study arent common (the researchers screened more than 200 to identify the 40 participants), and even in this carefully selected population, a 35% failure rate might be considered to be unacceptably high. DIFFERENTIAL EFFECTS OF LIFESTYLE INTERVENTIONS AND METFORMIN FOR PREVENTING TYPE 2 DIABETES The American Diabetes Association recommends intensive diet intervention and physical activity counseling for patients with impaired glucose tolerance or impaired fasting glucose and suggests that metformin can be considered for these patients ( http:// dx.doi.org /10.2337/dc15-S008 ). In a post hoc analysis of data from the Diabetes Prevention Program randomized trial ( www.jwatch.org /jw200202190000001 ), researchers determined in which patients lifestyle modification or metformin therapy was most likely to prevent the onset of frank diabetes. Their work appears on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. h454 ). Patients with impaired fasting glucose (a range of 95 to 125 mg/ dL) or abnormal glucose tolerance but not frank diabetes were randomized to a lifestyle modification program (with weight-loss and physical-activity goals), usual care plus 850mg of metformin twice /day , or usual care plus placebo. Of the 3000 patients, 20% developed type2 diabetes during a median follow-up of 3years. The patients were stratified into 4 groups according to their baseline risk for developing diabetes. The lifestyle-modification patients were less likely to develop diabetes than were any other patients: The 3-year absolute risk reduction was 30% for those at the highest risk (the number needed to treat in this group was 3.5) and 5% for those at the lowest risk (the number needed to treat in this group was 20). But for the metformin patients, only those at the highest risk benefited from drug therapy (the 3-year absolute risk reduction was 20% and the number needed to treat in the metformin group was 4.6). This study suggests that intensive diet and physical activity interventions lower the risk for developing type2 diabetes in all patients at elevated risk, whereas metformin lowers the risk only for those initially at highest risk. The researchers conclude that their results could decrease drug overuse and could help prioritize lifestyle programs for preventing type2 diabetes. VARENICLINE ISNT ASSOCIATED WITH DEPRESSION, SUICIDAL BEHAVIOR, OR DEATH Varenicline (trade name: Chantix) is effective for achieving smoking cessation. But since 2009, the Food and Drug Administration has required a black box warning about possible neuropsychiatric adverse events. In a meta-analysis on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. h1109 ), researchers systematically reviewed 40 randomized controlled trials (with durations between 1 and 52weeks) that involved 11,000 long-term smokers (average use was 20 cigarettes /day for 26years) to see whether excess neuropsychiatric adverse events were associated with the use of varenicline. The maximum dose of varenicline was 1mg twice /day . The risks for suicide or attempted suicide, suicidal ideation, depression, irritability, aggression, and death were similar in the varenicline users and the placebo users. Compared with the placebo users, the varenicline users had significantly higher risks for sleep disorders, insomnia, abnormal dreams, and fatigue, but a lower risk for anxiety. There was no evidence for a variation in the risk for depression or suicidal ideation by age, sex, ethnicity, smoking status, the presence or absence of psychiatric illness, or study sponsor. In this meta-analysis, varenicline use wasnt associated with an excess risk for depression, suicidal behavior, or death, compared with placebo. But varenicline was associated with sleep disturbances. Because the harms of smoking and the benefits of smoking cessation are well known, the researchers conclude that their findings suggest the benefits of varenicline for smoking cessation outweigh the as yet unproved risks of suicidal behaviour . ACETAMINOPHEN IS INEFFECTIVE FOR LOW BACK PAIN Acetaminophen is recommended as a first-line analgesic for low back pain and pain related to hip and knee osteoarthritis, but the evidence supporting this practice is weak. In a meta-analysis on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. h1225 ), researchers reviewed data from 13 randomized trials to evaluate the safety and efficacy of 3000 to 4000 mg/ day of acetaminophen vs . placebo in 3500 patients with knee or hip osteoarthritis and in 1800 patients with low back pain. In the patients with low back pain, acetaminophen was no more effective than placebo for pain and disability in the immediate term (up to 2weeks) or for pain, disability, and quality of life in the short term (up to 3months). The patients with hip or knee osteoarthritis who took acetaminophen had less immediate-term pain, but not disability, and less short-term pain and disability, compared with the placebo patients. Side effects, treatment withdrawals, medication adherence, and the use of rescue medications (like naproxen) were similar between the comparison groups, but the acetaminophen patients were more likely to have abnormal results on liver function tests (roughly 6 vs . 2%). In this meta-analysis, acetaminophen wasnt effective in patients with low back pain. Although the differences in pain and disability in the patients with osteoarthritis-related hip or knee pain were statistically significant, those effects were small (less than a 4mm difference on a 0 to 100mm scale) and probably not clinically meaningful (generally, a difference of 9 or moremm is considered to be clinically important). Notably, we dont know the long-term safety and efficacy of acetaminophen in patients with back pain or osteoarthritis-related hip or knee pain. MULTIDISCIPLINARY REHAB FOR CHRONIC LOW BACK PAIN Chronic low back pain results from multiple causes, both physiological and psychosocial. In a meta-analysis on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. h444 ), researchers systematically reviewed 40 randomized controlled trials to evaluate the effects of multidisciplinary rehabilitation vs . other treatments in 7000 patients with chronic low back pain (and an average pain duration of longer than a year). Multidisciplinary rehabilitation consisted of physical treatment (like heat, electrotherapeutic modalities, stretching, strengthening, and manual therapy) plus a psychological component, a social or work-related component, or both. The researchers found moderate-quality evidence that multidisciplinary rehabilitation was significantly more effective than usual care for long-term pain and disability, but not for long-term work absence; they found low-quality evidence that multidisciplinary rehabilitation was more effective than physical treatment for long-term disability and work absence, but not for long-term pain. In the two trials in which multidisciplinary rehabilitation was compared with surgery, outcomes were similar, except for adverse events, which were more common in the surgical patients. In this meta-analysis, multidisciplinary rehabilitation was better than usual care and physical treatments alone for most, but not all, outcomes and was the same as surgery in patients with chronic low back pain. Treatment that combines a physical component with psychosocial components (that address the many causes and perpetuators of pain) makes sense. But as the researchers note, multidisciplinary rehabilitation programs can be resource-intensive and costly, and cost-effectiveness analyses of these programs are needed. GOUT IS ASSOCIATED WITH LOWERRISK FOR ALZHEIMER DISEASE Although hyperuricemia (which is a precursor to gout) is a risk factor for cardiovascular disease, its been suggested that higher blood uric acid levels are also associated with a lower risk for neurodegenerative conditions like Parkinson disease and dementia. To determine the effect of gout on the risk for developing Alzheimer disease, researchers in North America used a medical-records database from the United Kingdom to compare 60,000 patients with gout and an average age of 65 and 240,000 patients without gout who were matched by age, sex, and body-mass index. Details appear on the website of the Annals of the Rheumatic Diseases ( http:// dx.doi.org /10.1136/annrheumdis-2014-206917 ). During a median follow-up of 5years, new cases of Alzheimer disease developed in 300 patients with gout and in 1900 matched controls without gout. After adjusting for multiple variables, the patients with gout were a quarter less likely to develop Alzheimer disease than were those without gout. The results were similar in subgroup analyses based on sex, age, social deprivation, and history of cardiovascular disease. Interestingly, the researchers conducted similar analyses for patients with and without osteoarthritis and found no association between osteoarthritis and the risk for Alzheimer disease. In this study, gout was associated with a lower relative risk for developing Alzheimer disease. Although the biological mechanisms arent clear, the researchers speculate that uric acid, which has antioxidant properties, prevents neuron death by suppressing the accumulation of toxic oxygen radicals. This study adds to the evidence of a neuroprotective role for uric acid. SIMULTANEOUS MODIFICATION OF MULTIPLE RISK FACTORS SLOWS COGNITIVE DECLINE IN OLDER ADULTSAT RISK FOR DEMENTIA Recent estimates suggest that about a third of the cases of Alzheimer disease might be attributable to seven modifiable risk factors, namely: Low education, hypertension, obesity, diabetes, inactivity, smoking, and depression. Efforts to prevent dementia by modifying one or two of these risk factors havent met with much success. To evaluate a more comprehensive approach, researchers in Finland randomized 1300 patients between the ages of 60 and 77 with risk factors for dementia and baseline cognitive function at or slightly below expected for age to a 2-year multidomain intervention or to general health advice (this was the control group). The intervention consisted of individual and group sessions for dietary counseling and cognitive training, supervised aerobic and muscle-strengthening exercises, and regular monitoring of vascular risk factors. Findings appear on the website of The Lancet ( http:// dx.doi.org /10.1016/ S0140- 6736(15)60461-5 ). At 2years, scores on a standard battery of neuropsychological tests improved from baseline in both of the groups, but the scores in the intervention patients improved 25% more than did those in controls thats a significant difference. The risk for overall cognitive decline was significantly greater in the control group. The intervention patients improved significantly more than did the controls on measures of executive functioning and processing speed, but not overall memory. The researchers note that small improvements in common problems like cognitive decline can have important implications for public health. This study population will be followed for another 7years to evaluate potential between-group differences in the incidence of frank dementia, which might have more dramatic public health implications.
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