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. Mark Preston, Dr. Mark Olfson, and the planning committee members reported that they had nothing to disclose. BASELINE PSA LEVEL PREDICTS SUBSEQUENT RISK FOR LETHALPROSTATE CANCER Both proponents and opponents of prostate-specific antigen (PSA) screening agree that too-frequent screening can result in an overdiagnosis of nonlethal prostate cancer and excessive downstream intervention. In several studies, low PSA levels in middle age were associated with a very low risk for developing lethal prostate cancer. In a nested case-control study in the August10 issue of the Journal of Clinical Oncology ( http:// dx.doi.org /10.1200/JCO.2016.66.7527 ), researchers used stored baseline blood samples collected between 1982 and 1984 from 20,000 men who participated in the Physicians Health Study. During 30years of follow-up, 70 men between the ages of 40 and 59 at baseline developed lethal prostate cancer (defined as fatal cancer or nonfatal metastatic cancer). PSA level at baseline strongly predicted subsequent risk for lethal prostate cancer. For example, in men who were 50 to 54years old at the baseline blood draw, the estimated 20-year cumulative incidence of lethal cancer was nearly 4% when PSA level was in the top 10th percentile (2.1 ng/ mL or higher), but only 0.3% when PSA level was below the median (lower than 0.9 ng/ mL). For men who were 55 to 59years old at the baseline blood draw, the estimated 20-year incidence of lethal cancer was about 6% when PSA level was in the top 10th percentile (3.0 ng/ mL or higher), but only 0.4% when PSA level was below the median (lower than 1.0 ng/ mL). Four years ago, the United States Preventive Services Task Force recommended against prostate-specific antigen screening ( www.jwatch.org /jw201206070000001 ). But for patients who choose screening, the researchers of the current study suggest that intervals between tests could be substantially lengthened (i.e., beyond annually) for the men whose PSA levels are below age-specific medians. They also suggest that screening could be stopped in men with PSA levels lower than 1.0 ng/ mL at the age of 60. Notably, guidelines from the American Cancer Society ( www. cancer .org /cancer/prostatecancer/moreinformation/prostatecancerearlydetection/prostate-cancer-early-detection-acs-recommendations ) and the American Urological Association ( https:// www. auanet .org /common/pdf/education/clinical-guidance/Prostate-Cancer-Detection.pdf ) now recommend less-than-annual screening for most men. ANOTHER STUDY OF PIOGLITAZONE USE AND RISK FOR BLADDER CANCER The evidence is mixed as to whether pioglitazone (trade name: Actos), which is an oral thiazolidinedione drug thats used for managing type2 diabetes, is associated with an excess risk for bladder cancer. In a retrospective cohort study on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. i3903 ), researchers in four European countries evaluated the risk for bladder cancer in nearly 60,000 patients older than 40 with type2 diabetes who started treatment with pioglitazone. The patients were matched (based on treatment history and propensity scores for factors related to pioglitazone use) with two separate cohorts of patients with type2 diabetes who were treated with glucose-lowering drugs other than pioglitazone. During an average follow-up of roughly 3years, the risk for bladder cancer in the pioglitazone group was the same as that in either of the unexposed cohorts. Plus, a longer duration of use (for example, more than 4years) and a higher cumulative dose of pioglitazone were not associated with an excess risk for bladder cancer. In this study, pioglitazone was not associated with an excess risk for bladder cancer. This is in contrast to a study published earlier this year that showed a rise in the risk for bladder cancer after only 2years of pioglitazone use ( www.jwatch.org /na40969 ). How might these conflicting studies be reconciled? The researchers of this study note that large studies with long follow-up have shown no association between pioglitazone and bladder cancer ( www.jwatch.org /na38578 ) and that some studies showing an excess risk have had methodological flaws. Even if pioglitazone confers an excess risk, the absolute risk is low. CAN ANTITNF THERAPIES BE STOPPED IN PATIENTS WITH RA? Biologic therapies like antitumor necrosis factor (TNF) agents have improved outcomes in patients with rheumatoid arthritis. But anti-TNF drugs are expensive and can have serious side effects, raising questions about how long patients need to stay on them and whether those whose disease is in remission can discontinue therapy. In an open-label study in the Augustissue of Arthritis & Rheumatology ( http:// dx.doi.org /10.1002/art.39626 ), researchers in the Netherlands randomized 800 patients who were in remission or had low disease activity for at least 6months to either stop treatment or continue treatment with their current anti-TNF therapy; the patients average age was 60 and two thirds were women. In the event of a disease flare, anti-TNF therapy could be restarted in the stop group or switched in the continuation group. Within a year, significantly more patients in the stop group experienced flares than did those in the continuation group (51% vs . 18%), based on a composite measure of disease activity. Among the patients in the stop group who restarted anti-TNF therapy after experiencing flares, nearly 90% regained low disease activity or remission. These results show that routinely stopping antitumor necrosis factor therapy is not an acceptable treatment strategy for patients with rheumatoid arthritis who are in remission or who have low disease activity. But half of the patients in whom treatment was stopped did not relapse, so additional research is warranted to see which patients are least likely to have flares when stopping therapy and to compare tapering with abrupt stopping. IN A REAL-WORLD SETTING, FLUTICASONE PLUS VILANTEROLLOWERED RISK FOR COPDEXACERBATIONS Often, patients in clinical trials of chronic obstructive pulmonary disease do better than real-world patients because of strict entry criteria, close follow-up, and better medication adherence. In an integrated comparative effectiveness trial on the website of the New England Journal of Medicine ( http:// dx.doi.org /10.1056/NEJMoa1608033 ), researchers in the United Kingdom evaluated the inhaled combination fluticasone furoate and vilanterol (trade name: Breo Ellipta) in a less rigorous, primary caresetting protocol. Nearly 3000 patients in general practices with COPD who needed daily therapy and had at least one exacerbation within the past year were randomized either to 100μg of inhaled fluticasone furoate plus 25μg of vilanterol once /day or to usual care. Usual care consisted of any combination of an inhaled corticosteroid, a long-acting β-agonist, and a long-acting muscarinic antagonist. The patients were followed for a year for COPD exacerbations that necessitated antibiotics, systemic steroids, or hospital admissions or visits. The average annual exacerbation rate was lower in the fluticasone-plus-vilanterol group than it was in the usual-care group (1.74 vs. 1.90 exacerbations yearly, P =0.02). The two groups were similar in the incidence of pneumonia or other safety outcomes. In a real-world setting, inhaled fluticasone plus vilanterol prevents some exacerbations of chronic obstructive pulmonary disease, compared with usual care, but whats unclear is whether this is due to the simple once-daily device, the study population (20% had asthma that would benefit from inhaled corticosteroids), or suboptimal treatment in some patients (119 patients got inhaled corticosteroid monotherapy without bronchodilators). A study in which once-daily combination fluticasone and vilanterol was compared with a once-daily antimuscarinic agent would be nice to see, but, for now, the debate continues on whether to use a long-acting muscarinic antagonist, a long-acting β-agonist plus a long-acting muscarinic agent, or a long-acting β-agonist plus an inhaled corticosteroid. This study was industry-funded. EFFECTS OF VASOPRESSIN vs . NOREPINEPHRINE ON RENALFUNCTION IN PATIENTS WITH SEPTIC SHOCK We dont really have much information to guide vasopressor choice in treating patients with septic shock. A trial from 2008, known by the acronym VASST, showed no benefit in adding vasopressin to norepinephrine ( www.jwatch.org /id200802270000001 ), but smaller studies have suggested improved renal function with the early use of vasopressin. In a study in the August2 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2016.10485 ), researchers in the United Kingdom used a 22 factorial design to randomize 400 patients with septic shock to vasopressin (titrated up to 0.06 U/ minute) or norepinephrine (titrated up to 12 μg /minute ) as a first vasopressor plus either hydrocortisone or placebo as a second intervention for those with persistent shock. The patients were randomized within 6hours of developing shock, and the vasopressors were titrated to maintain an average arterial pressure of 65mmHg to 75mmHg, with clinician latitude to adjust this target. At 28days after randomization, there were no differences in kidney failurefree days in the two vasopressor groups, although fewer patients in the vasopressin group got renal replacement therapy (25.4% vs . 35.3%). Organ failurefree days and 28-day mortality were similar in the two vasopressor groups, as well as in the steroid and the placebo groups. The results of this study should not change the treatment approach for patients with septic shock. Using steroids for patients with refractory shock (that is to say, persistent hypotension on two vasopressors) is still reasonable, but not beyond that setting. One might be tempted to construe that the difference in the rates of renal replacement therapy favors vasopressin, but this metric is difficult to interpret, because no standard criteria for starting renal replacement therapy were used in this study. For now, it seems appropriate to stick with norepinephrine as a first-line vasopressor. HIGHER LEVELS OF PHYSICAL ACTIVITY ARE ASSOCIATED WITH LOWER RISKSFOR SEVERAL DISEASES The World Health Organization recommends a minimum of 600 metabolic equivalent (MET) minutes every week for health benefits (for example, walking briskly [4.3 METs] for 30minutes for 5days each week). But we dont know much about dose-response associations between physical activity and the risks for various diseases. In a meta-analysis on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. i3857 ), researchers systematically reviewed 170 articles and quantified dose-response associations between total physical activity (including both leisure and work-related activity) and the risks for diabetes, ischemic heart disease, ischemic stroke, breast cancer, and colon cancer. Compared with the disease risks in insufficiently active people (those whose physical activity level falls below 600 MET minutes /week ), the risks for disease were lower, in dose-response fashion, in minimally active people (between 600 and 3999 MET minutes /week ), moderately active people (between 4000 and 7999 MET minutes /week ), and highly active people (8000 or more MET minutes /week ). The risks were 3% to 14% lower for breast cancer, 10% to 20% lower for colon cancer, and about 15% to 25% lower for heart disease, stroke, and diabetes; the lowest risks for each disease were seen in the people with the highest level of activity. In this analysis, people who achieved levels of physical activity several times higher than the minimum recommended by the World Health Organization had significantly lower risks for diabetes and several cancer and cardiovascular outcomes. But most of the relative risk reductions were seen when inactive or low-active levels were raised to between 3000 MET minutes /week and 4000MET minutes /week (e.g., vigorous stationary bicycling [11 METs] for 45minutes daily), with diminishing returns at higher activity levels. Although the included studies were generally controlled for some potentially confounding factors, residual confounding in which the level of exercise is a marker for other unmeasured healthful attributes might explain some of the findings. ELECTRIC FANS DONT COOL ELDERSEXPOSED TO EXTREME HEATAND HUMIDITY Heat and humidity can be dangerous for older adults, who often use electric fans to try to cool off. In a small study in the September6 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2016.10550 ), researchers asked nine patients with an average age of 68 (3 men and 6 women) to sit for about 2hours in a room maintained at a temperature of 42°C (thats 107.6°F). The patients wore shorts (plus sports bras for women). After 30minutes at a relative humidity of 30%, the relative humidity in the room was increased by 2% every 5minutes until it reached 70%. On separate randomly assigned days, the patients sat in the room with or without a 16-inch electric fan facing them from 1 meter away. The patients were allowed no fluid intake. During the 100-minute period of increasing humidity, the patients heart rate rose from roughly 75 beats per minute to 100 beats per minutes without the fan and to 104 beats per minutes with the fan. Core temperature rose from roughly 36.3°C to 37.6°C without the fan and to 37.8°C with the fan. This study suggests that a seemingly sensible approach using an electric fan on very hot humid days has counterintuitive effects in older people. The small increase in temperature or heart rate with fan use is not clinically important, but the lack of decline in these measures is. Clinicians should advise their older patients that an electric fan alone has no cooling value during conditions of extreme heat and humidity. SYNCOPE AND UNEXPLAINED FALLS IN ELDERS WITH DEMENTIA Unexplained falls and a transient loss of consciousness pose diagnostic challenges in older patients with dementia. In a prospective study in the August Journal of the American Geriatrics Society ( http:// dx.doi.org /10.1111/jgs.14225 ), researchers in Italy sought to determine the cause of unexplained falls or suspected syncope in 360 patients with dementia and an average age of 84 who were referred to special geriatric units. A standardized evaluation included a comprehensive history-taking and physical examination, electrocardiography, orthostatic blood pressure measurement, and in selected cases echocardiography, Holter monitoring, carotid sinus massage, and tilt testing. These evaluations conformed to guidelines by the European Society of Cardiology ( http:// dx.doi.org /10.1093/eurheartj/ehp298 ). A plausible cause of syncope was identified in 90% of the patients referred with suspected syncope, in 45% of the patients referred for unexplained falls , and in 90% of the patients referred for both reasons. So a presumptive cause of syncope was confirmed in two thirds of the patients overall. Symptomatic orthostatic hypotension was discovered in about half of the 242 patients with final diagnoses of syncope, and a variety of other causes accounted for the other half. Hypotensive medications were considered to be responsible for about half of the orthostatic cases. In older patients with dementia, many falls result from a combination of musculoskeletal and neurological factors that produce gait instability, and these factors are not easily correctible. But potentially remediable causes in particular, orthostatic hypotension should not be overlooked. Lying and standing blood pressures should be measured routinely in older patients who take hypotensive drugs, and the goals of drug therapy should be reevaluated in patients with substantial orthostatic changes. VIRTUAL REALITY, ADDED TO TREADMILL TRAINING, LOWERSFALLRISK IN ELDERS Often, older adults fall due to problems negotiating obstacles; these falls can involve both cognitive and motor deficits. Interventions to prevent falls have targeted both types of impairment, but usually separately. To look at them together, researchers enrolled nearly 300 community-living adults between the ages of 60 and 90 who reported at least two falls in the past 6months; the researchers randomized them to either traditional treadmill training or training on a treadmill outfitted with a virtual reality screen that displayed the actual position of the patients feet and a program of simulated obstacles and distractors. The patients attended three 45-minute sessions every week for 6weeks; speed and the duration of walking were progressively increased for all of the patients. The virtual-reality group was presented with progressively more difficult motor and cognitive challenges. Results appear on the website of The Lancet ( http:// dx.doi.org /10.1016/ S0140-6 736(16)31325-3 ). The patients in both of the groups reported fewer falls in the 6months after training than in the 6months before training (means, 6 falls vs . 12 falls in the virtual reality group; 8 falls vs . 11 falls in the treadmill-only group). The difference between the groups and the difference over time in the virtual-reality group were significant. Several gait measures that contribute to the risk for falls were significantly better immediately after training in the virtual-reality group than in the treadmill-only group, and some of these differences were still present 6months later. The patients with Parkinson disease benefited more than the patients in other subgroups on some measures. In this study, the integration of cognitive and motor training using virtual reality lowered the incidence of falls in older at-risk adults. The intervention seems to be safe and relatively inexpensive and could be applied widely if further study confirms its benefits. IMMUNIZATION EXEMPTIONS FOR CHILD CARE AND SCHOOL ATTENDANCE: AAP POLICY STATEMENT The level of distrust of childhood vaccines is growing, despite their obvious success. Some parents decline vaccinations for their children and request nonmedical (personal belief) exemptions to comply with school requirements. All of the states in the United States, but three (namely, Mississippi, West Virginia, and California), allow for these nonmedical exemptions. Truecontraindications to some vaccinations do exist, andchildren who have them need medical exemptions for school attendance. The American Academy of Pediatrics released a policy statement regarding these issues in the Septemberissue of Pediatrics ( http:// dx.doi.org /10.1542/peds.2016-2145 ). Among the Academys positions are: A refusal to vaccinate not only places the individual child at risk, but also possibly the entire community, as a vaccinated herd is essential to avoid most vaccine-preventable diseases. Immunization requirements are an effective way to protect both the individual child and the community. The American Academy of Pediatrics supports laws that enforce the certification of immunization for all children. The American Academy of Pediatrics supports valid medical exemptions to specific immunizations when appropriate. The American Academy of Pediatrics urges all states to enact laws to eliminate nonmedical exemptions from immunization requirements. Personal belief exemptions that allow unvaccinated children to attend school place communities at risk for outbreaks of communicable diseases and jeopardize the health of children. This policy lays out a clear and convincing argument to eliminate these exemptions and supports pediatricians in their efforts to make sure that all of their patients are vaccinated. SHOULD PATIENTS WITH NONISCHEMIC HF RECEIVE ICDs? Guidelines strongly recommend considering implantable cardioverterdefibrillator therapy for patients with severe left-ventricular systolic dysfunction, regardless of the cause. But the evidence for a survival benefit with these devices is largely confined to left-ventricular systolic dysfunction thats related to coronary artery disease, with some data suggesting a benefit when left-ventricular systolic dysfunction has a nonischemic cause ( www.jwatch.org /jw200502080000001 ). In a study on the website of the New England Journal of Medicine ( http:// dx.doi.org /10.1056/NEJMoa1608029 ), researchers randomized 1100 symptomatic patients with nonischemic heart failure (an ejection fraction of 35% or lower) to either cardioverterdefibrillator implantation or usual care. The patients median age was 64 and three quarters were men; all of the patients got evidence-based medical therapies. Median follow-up was almost 6years. All-cause mortality was statistically similar in the two groups at around 22% although implantable cardioverterdefibrillator therapy conferred a significant survival benefit in the patients younger than 59. Sudden cardiac death was significantly less common with the device than with usual care (4.2% vs . 8.3%), but not enough to show an advantage in cardiovascular-related death overall. Of the implantable cardioverterdefibrillator group, 12% got appropriate shocks, 6% got inappropriate shocks, 15% needed battery replacements, and 5% had their devices permanently removed or deactivated because of infection or patient preference. Among patients with nonischemic left-ventricular systolic dysfunction, cardioverterdefibrillator implantation lowered the risk for sudden cardiac death, but not enough to yield an overall survival benefit. This trials relatively low incidence of sudden cardiac death certainly reflects a pervasive use of evidence-based medical therapies. Given the risks of implantable cardioverterdefibrillator-related complications, infection, and inappropriate shocks, these findings should be used to support shared decision-making between clinicians and their patients with nonischemic left-ventricular systolic dysfunction ( http:// dx.doi.org /10.1056/NEJMe1609826 ). This study was partly industry-funded. FUNCTIONAL TESTING TO REDUCE UNNECESSARY ANGIOGRAPHY? Often, patients with suspected coronary heart disease and a high pretest probability of disease undergo invasive angiography, but can functional testing prevent unnecessary angiograms that do not show significant obstruction? In a study on the website of JAMA ( http:// dx.doi.org /10.1001/jama.2016.12680 ), researchers in the United Kingdom sought to find out; they randomized 1200 stable patients 30 or older with chest pain and suspected coronary heart disease (range of pretest probability based on Duke scoring, 10%90%; mean, 50%) from six centers to one of three strategies for guiding care, namely: Functional testing with cardiac magnetic resonance Functional testing with myocardial perfusion scintigraphy U.K. National Institute for Health Care (NICE) guidelines, in which lower-risk patients (PP, 10%29%) predominantly undergo coronary computed tomographic angiography, moderate-risk patients (PP, 31%60%) undergo myocardial perfusion scintigraphy, and highest-risk patients move directly to angiography Unstable patients, those with past myocardial infarction or revascularization, and those with recent normal myocardial perfusion scintigraphy or coronary CT angiography results were excluded from the study. After a year, 40% of the patients in the National Institute for Health Care group had undergone angiography, compared with 18% in the cardiac-magnetic-resonance group and 16% in the myocardial-perfusion-scintigraphy group. The rates of unnecessary angiograms (defined as normal fractional flow reserve in all vessels ≥2.5mm in diameter) were 30% in the National Institute for Health Care group, 8% in the cardiac-magnetic-resonance group, and 7% in the myocardial-perfusion-scintigraphy group. Positive angiography rates were not significantly different. Major adverse coronary events were reported in 2.5% of the National Institute for Health Care group and in 3.1% of the other groups thats not a significant difference. Functional testing with either cardiac magnetic resonance or myocardial perfusion scintigraphy led to lower rates of angiography without a significant difference in major adverse coronary events, possibly because the National Institute for Health Care guidelinebased pretest probability overestimated the actual risk. The researchers note that the difference in the rates of unnecessary angiography between functional testing and National Institute for Health Care-guided testing was most striking in the high-risk patients (9.4% vs . 62.2%). But these rates were also different (although not statistically significantly so) even in lower-risk patients (4.8% and 11.5%, respectively), which is similar to earlier findings from the PROMISE study of anatomical testing vs . functional testing ( www.jwatch.org /na37279 ). Cardiac magnetic resonance and myocardial perfusion scintigraphy-guided outcomes in the current study were similar. REVERSING ANTICOAGULANT-ASSOCIATED BLEEDING WITH ANDEXANET Andexanet is a recombinant decoy protein that binds tightly to the active site of antifactor Xa anticoagulants; recently, it was shown to rapidly reverse the anticoagulant effects of rivaroxaban (trade name: Xarelto) and apixaban (trade name: Eliquis) in healthy older volunteers ( www.jwatch.org /na39557 ). To examine the safety and the efficacy of andexanet in reversing anticoagulant-associated bleeding, researchers studied 70 patients with an average age of 77 who had major gastrointestinal bleeding, intracranial bleeding, or other bleeding that was associated with the use of rivaroxaban, apixaban, or enoxaparin. Andexanet was given as a bolus dose and a 2-hour intravenous infusion. Efficacy was examined in the subset of patients with elevated blood levels of these anticoagulants. Findings appear on the website of the New England Journal of Medicine ( http:// dx.doi.org /10.1056/NEJMoa1607887 ) and include: Median antifactor Xa levels fell dramatically and hemostatic efficiency was rated as excellent or good in about 80% of the rivaroxaban and the apixaban patients (26 and 20 patients, respectively). In 1 patient given enoxaparin, antifactor Xa activity declined substantially and bleeding was controlled. Thrombotic events were seen in 12 patients, but only 1 had a therapeutic dose of anticoagulant restarted before the event. There were 10 deaths (15%); 6 were cardiovascular-related. Anticoagulants often accumulate and incite bleeding in older patients with impaired renal function and other comorbidities. Andexanet rapidly reduced elevated antiXa factor levels and controlled bleeding in most of the patients. But the Food and Drug Administration has withheld approval of the drug pending additional manufacturing data and further experience with enoxaparin, so the current clinical trial is continuing. This study was industry-sponsored. NEXT PHASE IN ANTICOAGULATION FOR CARDIOVERSION OF PATIENTS WITH AF In patients undergoing elective cardioversion for atrial fibrillation, standard anticoagulation lasts for 3weeks before and 4weeks after the procedure. When a transesophageal echocardiogram excludes left-atrial thrombus, cardioversion can be performed safely without preprocedural (but not without postprocedural) anticoagulation. In a multinational study on the website of The Lancet ( www. thelancet .com /journals/lancet/article/PII S0140-6 736(16)31474-X/fulltext ), researchers randomized 2200 patients with atrial fibrillation lasting anywhere from 2days to 1year who were undergoing elective cardioversion to either enoxaparinwarfarin or the direct oral anticoagulant edoxaban (trade name: Savaysa). Local researchers chose whether to use 3weeks of preprocedural anticoagulation or a more-immediate approach guided by transesophageal echocardiography. The incidence of the primary endpoint which was stroke, systemic embolism, myocardial infarction, or cardiovascular-related mortality was statistically similar with edoxaban and the enoxaparinwarfarin combination at around 1%, as was the incidence of major bleeding and clinically relevant nonmajor bleeding (1% in both groups). The choice of 3weeks of preprocedural anticoagulation or transesophageal echocardiogram-guided cardioversion did not affect the findings. These results show that anticoagulation with edoxaban compares favorably with warfarin in patients with atrial fibrillation who undergo elective cardioversion. This treatment effect likely translates to other direct oral anticoagulants ( www. thelancet .com /journals/lancet/article/PII S0140-6 736(16)31410-6/fulltext ). The trial also documents low incidences of thromboembolism and bleeding in well-managed patients undergoing cardioversion, regardless of whether a 3-week preprocedural anticoagulation or a quicker approach guided by transesophageal echocardiography is employed. Given the ease of use of direct oral anticoagulants, this study further weakens the position of warfarin as an anticoagulant in patients with atrial fibrillation. This study was manufacturer-funded. A PROFILE OF NONSTENOTIC CAROTID PLAQUES IN CRYPTOGENIC STROKE Most patients with ischemic stroke undergo carotid duplex ultrasound, echocardiography, and cardiac monitoring for atrial fibrillation. When testing doesnt reveal a likely mechanism for the stroke, its labeled cryptogenic . Recently, the term embolic stroke of unknown source has been used for embolic-appearing ischemic lesions without a definite cause. In an observational study in the August16 issue of Neurology ( http:// dx.doi.org /10.1212/WNL.0000000000002978 ), researchers used computed tomography angiography to identify the thickness of nonstenotic (<50% stenosis) carotid plaques and compared plaques that were ipsilateral vs . contralateral to the embolic stroke of unknown source event. Among 85 patients with embolic stroke of unknown source and a median age of 70, plaques at least 5mm thick were present in 11% of the ipsilateral vessels and in 1% of the contralateral vessels, and plaques at least 3mm thick were present in 35% of the ipsilateral vessels and in 15% of the contralateral vessels; these differences were statistically significant. The greater thickness of ipsilateral plaques persisted when noncalcified portions of the plaques were evaluated. The degree of stenosis was similar in the plaques that were ipsilateral or contralateral to the embolic stroke of unknown source event. These findings show an association between the location of large, nonstenotic carotid plaques and embolic-appearing strokes, but do not establish causation. Exploring whether these nonstenotic plaques are associated with microemboli to the brain would be worthwhile. Given that these lesions are not hemodynamically significant, carotid revascularization isnt warranted, but medical therapy can be started or intensified to manage them. BP VARIABILITY IS ASSOCIATED WITH ADVERSE CV OUTCOMES Most studies of blood pressure as a cardiovascular risk factor have used average blood pressure, but evidence suggests that blood pressure variability, independent of average blood pressure, might also be important ( www.jwatch.org /na38625 ). In a meta-analysis on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. i4098 ), researchers systematically reviewed 19 prospective cohort studies and 17 clinical trials to evaluate the associations between adverse cardiovascular events and blood pressure variability in the long term (measured at 5 or more clinic visits), midterm (measured at home at least 12 times on 3 or more days), and short term (measured by ambulatory monitoring for up to 24hours, with 14 or more daytime readings). Studies that did not adjust for average blood pressure were excluded. In the studies with a low risk for bias, long-term systolic blood pressure variability was significantly associated with up to 20% higher risks for all-cause death, cardiovascular-related death, stroke, and coronary heart disease events. Midterm systolic blood pressure variability was associated with a 15% higher risk for all-cause death, and daytime short-term systolic blood pressure variability was associated with a roughly 11% higher risk for all-cause death, cardiovascular-related death, and stroke. In this analysis, systolic blood pressure variability was associated with an excess risk for adverse events, independent of average blood pressure. But theres a problem in applying these results clinically: Theres no standard definition of important blood pressure variability; blood pressure variability was calculated in various ways in these studies. Even so, the findings might be useful when evaluating cardiovascular risk in patients with highly variable, but relatively normal, average systolic blood pressure or in those with cardiovascular risk estimates close to treatment thresholds (for example, triggering treatment in patients with highly variable blood pressure and borderline risk). DOES CPAP LOWER CV RISK? Its clear that obstructive sleep apnea is a risk factor for cardiovascular disease, but whether continuous positive airway pressure (CPAP) lessens that risk is not clear. To shed light on the topic, researchers randomized nearly 3000 patients between the ages of 45 and 75 (mean age, 61) 80% were men either to CPAP plus usual care or to usual care alone. The patients were recruited from seven countries and were eligible if they had both moderate-to-severe obstructive sleep apnea and coronary artery disease or cerebrovascular disease. Findings appear in the September8 New England Journal of Medicine ( http:// dx.doi.org /10.1056/NEJMoa1606599 ). With an average follow-up of 4years, the primary endpoint which was a composite of cardiovascular-related death, myocardial infarction, stroke, or hospitalization for heart failure, acute coronary syndrome, or transient ischemic attack was confirmed in 17% of the CPAP group and in 15% of the usual-care-only group thats not a significant difference. There was no significant heterogeneity across the subgroups. Sleepiness and other symptoms were improved by CPAP. This study is particularly important because about half of patients with cardiovascular disease have obstructive sleep apnea. Cardiovascular risk was not lessened by continuous positive airway pressure. Even so, some sleep apnearelated symptoms improved, which might lead some patients to try this treatment. CPAP FOR NONSLEEPY OBSTRUCTIVE SLEEP APNEA? In a study of nearly 3000 patients with obstructive sleep apnea and cardiovascular disease, treatment with continuous positive airway pressure (CPAP) did not improve cardiovascular outcomes, but did improve snoring, daytime sleepiness, quality of life, and mood ( www.jwatch.org /na42168 ). That trial excluded patients with severe daytime sleepiness, but permitted the enrollment of nonsleepy or mild-to-moderately sleepy patients. In a study in the September1 American Journal of Respiratory and Critical Care Medicine ( http:// dx.doi.org /10.1164/rccm.201601-0088OC ), researchers randomized 240 patients with recently revascularized coronary disease and obstructive sleep apnea (apnea-hypopnea index ≥15 /hour ) but exclusively without daytime sleepiness to either CPAP or no CPAP. After a median follow-up of about 5years, the incidence of the primary composite cardiovascular endpoint (namely, repeat revascularization, myocardial infarction, stroke, or cardiovascular-related mortality) was similar in the two groups (18% vs . 22%; P =0.45). But those who used CPAP at least 4hours/night had significantly lower cardiovascular risk than those who did not get treatment or who used CPAP for less than 4hours/night (hazard ratio, 0.29). Of note, 30 CPAP patients returned their devices within 3months of enrollment. Among patients with obstructive sleep apnea, but without daytime sleepiness, continuous positive airway pressure showed no significant benefit for cardiovascular outcomes. Although the patients who adhered to CPAP therapy did seem to benefit, the researchers note that the on-treatment analysis should be interpreted with caution, because adherence to CPAP could be a marker for other factors associated with better outcomes. Importantly, in the much-larger trial in the New England Journal of Medicine , CPAP did not improve cardiovascular outcomes regardless of adherence, and the average Epworth sleepiness score in that trial (7.4, on a 24-point scale) was not so different from that of the current study (5.5). Editorialists note ( http:// dx.doi.org /10.1164/rccm.201603-0484ED ) that interventions are needed to optimize adherence and to study therapies for obstructive sleep apnea other than CPAP (like mandibular advancement devices). At least for now, treatment for obstructive sleep apnea should be prescribed to improve daytime sleepiness and other symptoms of obstructive sleep apnea, but it might not improve cardiovascular outcomes. TREATMENT FOR DEPRESSION IN U.S.ADULTS: OUT OF ALIGNMENT? The accuracy of a diagnosis of depression in adults is a continuing concern, especially in light of substantially higher antidepressant use in recent years. To evaluate the association between depression diagnosis and treatment for depression in adults in the United States, researchers looked at data on nearly 50,000 adults who responded to national medical expenditure surveys in 2012 and 2013; the surveys included a two-question depression screen. Findings appear on the website of JAMA Internal Medicine ( http:// dx.doi.org /10.1001/jamainternmed.2016.5057 ). Among those surveyed, 8.4% screened positive for depression, ranging from nearly 4% in the group with the highest income to 18% in the group with the lowest income; only 30% of the patients who screened positive got any treatment for depression during the survey year. Among the 8% of all of the patients who got some type of depression treatment, only about 30% screened positive for depression; another 20% had other types of severe psychological distress. Most of the patients who got treatment for depression did so from general medical professionals (73%); these patients usually got antidepressants and rarely got psychotherapy. This study, which used survey data based on patient recall, raises many questions. The 8.4% prevalence of screen-positive depression is low compared with that in most large epidemiologic studies of depression. The two-question depression screen generally has high sensitivity, but low specificity, so the fact that many screen-positive patients got no treatment might not reflect poor care. Nearly half of all of the patients treated for depression were screen-negative and reported minimal psychological distress; this might reflect antidepressant use for indications other than depression, or it might be a sign that depression treatment was successful.
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