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NEJM Journal Watch

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Course Description

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. Venkatesh Thiruganasambandamoorthy, Dr. Henry Blumberg, and the planning committee members reported no relevant financial conflicts of interest. CURRENT USE OF PRESCRIBED NSAIDsIS ASSOCIATED WITH ELEVATED RISK FOR HF Nonsteroidal anti-inflammatory drugs are associated with an excess risk for heart failure. In a study on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. i4857 ), researchers used healthcare databases in four countries in Europe to evaluate the association between NSAID use and hospital admission for heart failure. Among nearly 8 million adults who started treatment with prescription NSAIDs between 2000 and 2010, researchers identified 90,000 cases with an average age of 77 and heart failure-related hospital admission; these patients were matched by age, sex, and their year of study entry with more than 8 million controls. The risk for heart failure-related hospital admission was significantly higher with current NSAID use (meaning within the past 2weeks) than with prior use (adjusted odds ratio, 1.2). In analyses of individual NSAIDs, the current use of seven traditional NSAIDs and two cyclooxygenase (COX)-2 inhibitors was associated with significantly higher risks for hospital admission. (The seven NSAIDs are: Diclofenac, ibuprofen, indomethacin, ketorolac, naproxen, piroxicam, and nimesulide [which is not available in the United States] and the two COX-2 inhibitors are: Etoricoxib [which is not approved by the Food and Drug Administration] and rofecoxib [trade name: Vioxx, which was withdrawn from the market].) Significant doseresponse associations were found for diclofenac, etoricoxib, indomethacin, naproxen, and rofecoxib. In this study, the current use of many prescribed nonsteroidal anti-inflammatory drugs was associated with an elevated risk for heart failure-related hospital admission. Although these results are subject to confounding, they are biologically plausible: NSAIDs inhibit prostaglandin synthesis and can impair renal function, potentially triggering heart failure in susceptible patients. Notably, some NSAIDs (like ketoprofen) and COX-2 inhibitors (like celecoxib) were not associated with an increased risk. AF IS ASSOCIATED WITH ADVERSE CVOUTCOMES BEYOND STROKE The mainstays of managing patients with atrial fibrillation include rate control and anticoagulation to prevent stroke, but atrial fibrillation is also associated with other adverse cardiovascular outcomes. In a meta-analysis on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. i4482 ), researchers in the United Kingdom systematically reviewed 100 cohort studies and examined the associations between atrial fibrillation and the risks for various adverse cardiovascular events, kidney disease, and early mortality in nearly 10 million patients (including 600,000 with atrial fibrillation). During a median follow-up of up to 6years, atrial fibrillation was associated with significantly higher risks for peripheral artery disease, all-cause death, ischemic heart disease, chronic kidney disease, sudden cardiac death, major adverse cardiovascular events, cardiovascular-related death, stroke, and heart failure (relative risks ranging from 1.3 for peripheral artery disease to 5.0 for heart failure). The results were consistent across all of the patient subgroups (for example, categorized by age or a history of ischemic heart disease or stroke) and across various study characteristics (like study population, study location, and follow-up duration). In this meta-analysis, atrial fibrillation was associated with a higher risk for a wide range of adverse nonstroke outcomes. But these associations do not establish causality; as the researchers note, atrial fibrillation could be acting as a marker for an underlying predisposition to adverse cardiovascular and kidney outcomes. So clinicians should evaluate the risks for these other adverse outcomes when they consider interventions beyond rate control and stroke prevention in patients with atrial fibrillation. NEW SYNCOPE RISK SCORE Several groups have developed decision tools each with limitations to predict adverse outcomes in patients with syncope. The latest effort is a prospective cohort study that involved 4,000 adults who presented to six emergency departments in Canada within 24hours after syncopal events. Details appear in the September6 issue of CMAJ ( http:// dx.doi.org /10.1503/cma j. 151469 ). During a month of follow-up, serious adverse events (including death and several specified cardiac and noncardiac events) were seen in nearly 4% of the patients. Using multivariable analysis and additional statistical techniques to confirm the validity of the selected predictive variables, the researchers derived a risk score (ranging from −3 to +11) based on nine clinical predictors. The risk for a serious adverse event ranged from 0.4% (in the patients with a score of −3) to 40% (in those with scores of 6 or higher). No decision rule for syncope can be perfect; for example, even labeling an event as syncopal isnt always straightforward. Plus, this new scoring system includes two variables that are historical (and open to some subjectivity) and two variables that depend on the accuracy of a final diagnosis in the emergency department. Even so, this work represents the largest reported prospective study of syncope (according to the authors), and it was performed very carefully. If validated in other populations, this scoring system might become a useful clinical tool to guide decision-making on further testing and the need for hospital admission. The nine predictors and their associated point values: ED diagnosis of vasovagal syncope, minus 2 points; predisposition to vasovagal symptoms, minus 1 point; abnormal QRS axis, QRS duration >130 milliseconds, and history of heart disease, plus 1 point each; any systolic blood pressure recorded in the ED of <90mmHg or >180mmHg, elevated troponin level, corrected QT interval >480 milliseconds, and ED diagnosis of cardiac syncope, plus 2 points each. NEUROLOGICAL SUDDEN DEATH IS NOTRARE Many cases of sudden death do not result in an autopsy and are assumed to be of cardiac origin. In a study on the website of Neurology ( http:// dx.doi.org /10.1212/WNL.0000000000003238 ), researchers gathered detailed information (including autopsies) at the time of death in 340 cases categorized as sudden cardiac death by the medical examiner that occurred during 25months in 2011 through 2013. Five percent were judged to be sudden neurological deaths caused by intracranial hemorrhage (8 cases), epilepsy (6cases), aneurysmal subarachnoid hemorrhage (2 cases), acute ischemic stroke (1 case), and aspiration in a patient with Huntington disease (1 case). The patients with histories of stroke or transient ischemic attack were not at a significantly greater risk for neurological death than were other patients (although the study was underpowered to evaluate this factor). The use of antithrombotic medication was a clear risk factor (odds ratio, 3.9). Of the 15 deaths in patients with epilepsy, 40% were caused by epilepsy, and the rest were caused by cardiac or other causes. Sudden neurological deaths were the second most common noncardiac cause of death, after drug overdose. Usually, sudden death is assumed to be of cardiac origin and is only infrequently pursued with autopsy examination. But this study suggests that cases of neurological death can sometimes be misclassified as cardiac deaths. Some deaths in large cardiovascular trials might have been similarly misclassified. ACUPUNCTURE FOR ALLEVIATINGCHRONIC SEVERE FUNCTIONAL CONSTIPATION Acupuncture has been used to manage chronic constipation, but evidence of its effectiveness is limited. In a multicenter study on the website of the Annals of Internal Medicine ( http:// dx.doi.org /10.7326/M15-3118 ), researchers in China randomized 1100 patients between the ages of 17 and 85 (three quarters were women) with chronic severe functional constipation (meaning fewer than 3 complete spontaneous bowel movements a week) to either electroacupuncture or sham electroacupuncture; the patients underwent about 30 sessions during 2months and were followed for another 3months after treatment ended. At baseline, the average number of weekly bowel movements was approximately 0.4 in both of the groups. At 2months, increases from baseline in average weekly bowel movements were 1.8 in the acupuncture group and 0.9 in the sham acupuncture group thats a significant difference. The differences between the two groups stayed significant through the end of follow-up. The proportion of patients who had three or more average weekly bowel movements during follow-up was significantly greater in the acupuncture group than in the sham acupuncture group (38% vs . 14%). Past studies have suggested that acupuncture at specific acupuncture points can stimulate the distal colon via parasympathetic activation. This study showed that electroacupuncture, compared with a sham procedure, eased chronic severe functional constipation substantially in about a quarter of the patients who underwent the treatment. For patients who are open to trying this approach, a trial of acupuncture could be safe and potentially beneficial, although its long-term efficacy has not been established. INTRA-ARTICULAR CELLULAR THERAPYFOR KNEE OA AND CARTILAGEDEFECTS Search the Internet for cell + therapy + knee and youll discover many doctors and clinics that offer intra-articular stem cell injections for knee osteoarthritis and cartilage defects. Typically, the cells are harvested from blood, bone marrow, or fat, and the cells might be combined with platelet-rich plasma. To examine the evidence supporting intra-articular cellular therapy, researchers conducted a systematic review, the results of which appear in the September21 issue of The Journal of Bone & Joint Surgery ( http:// dx.doi.org /10.2106/JBJS.15.01495 ). They found six studies that met their search criteria: Four randomized trials without blinding, one prospective cohort study, and one case-control study (including a total of 300 knees; half got the intervention). Three of the studies involved patients with osteoarthritis, and three involved patients with focal cartilage defects . Because the studies were so heterogeneous in methodologies, interventions, the selection of controls, and endpoints, a meta-analysis could not be performed. Both the intervention and the control groups tended to improve, with modestly better outcomes in the intervention groups for some (but not all) measures. Overall study quality was poor. Because of the limitations of this review, the researchers were not able to draw any conclusions about the efficacy of cellular therapy for structural knee problems. Maybe these treatments provide some benefit, but if they do, we dont yet have high-quality supporting evidence. Typically, intra-articular stem cell therapy is not covered by insurance; on the websites of several clinics that offer this treatment, there are quotes for out-of-pocket costs that range from US$3,000 to US$8,000 for treating one joint. WEARABLE ELECTRONIC MONITORING TECHNOLOGIES: NOT A MAGIC SOLUTION TO WEIGHT LOSS Wearable multisensor devices can provide feedback to patients about physical activity and energy expenditure. To explore whether this kind of technology can enhance standard behavioral weight-loss counseling in a younger patient population, researchers enrolled 470 overweight or obese patients between the ages of 18 and 35 in a clinical study in the September20 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2016.12858 ). The patients participated in a typical diet and exercise counseling program for 6months and were then randomized either to wear a commercially available activity monitor on the upper arm (this was the intervention group) or to continue the counseling program without the wearable device (this was the control group). The wearable technology provided feedback on physical activity and energy expenditure as well as the self-monitoring of dietary intake. All of the patients got weekly or monthly group educational and counseling sessions, monthly telephone follow-up, and weekly text messages, all of which promoted lower calorie intake and moderate-to-vigorous physical activity. At 2years, reductions in average calorie intake were similar in the two groups (at roughly 400kcal /day to 500kcal /day ), as were overall increases in average physical activity (roughly 5minutes /week to 35minutes /week ), although, at some evaluations, the intervention group actually showed decreases in physical activity. Average weight loss was modest in both of the groups, with significantly greater weight loss in the control group than in the intervention group (5.9kg vs. 3.5kg). This type of regular electronic feedback did nothing to improve what was already a disappointing level of weight loss, given the labor-intensive nature of the behavioral counseling program. The researchers offer no speculation on why the intervention group actually lost less weight than did the control group. DO PHYSICIANS IN AMBULATORY CARE SPEND MORE TIME WITH THE EMR THAN WITH PATIENTS? Outpatient practices have weathered substantial changes during the past decade, and these changes have placed new demands on physicians time. In a study on the website of the Annals of Internal Medicine ( http:// dx.doi.org /10.7326/M16-0961 ), researchers directly observed 60 doctors in 16 primary care or specialty outpatient practices (namely, family medicine, internal medicine, cardiology, and orthopedics); the time spent on various activities during the clinical day was documented. Plus, 20 doctors also kept after-hours diaries. Fifteen practices mandated the use of electronic medical record systems. Trained observers recorded the time each doctor spent on various activities. Physicians spent a third of their total time on direct clinical interactions (27% with patients and 6% with clinical staff when patients were not present). Half of physicians time was spent on electronic medical records or desk work (38% on documentation and review activities, 6% on test results, and 2% on medication orders). Administrative and other tasks comprised the rest of the day. Nearly 30 doctors none of whom was a primary care physician used documentation support (dictation or documentation assistants). The doctors without any documentation support spent the lowest proportion of time on direct contact with patients (23%); direct contact accounted for 30% of their time among the doctors with dictation services and for more than 40% of their time among the doctors with documentation assistants. The doctors who kept after-hours diaries reported an average of an additional 1.5hours of work every day, with 70% of those hours attributed to working with electronic medical records. Unsurprisingly, for every hour of direct face time with patients, physicians spent nearly 2hours on electronic medical records. Although documentation support services might alleviate some of the burden, interestingly, none of the primary care practices provided these services for their doctors ( http:// dx.doi.org /10.7326/M16-1757 ). RACIAL DIFFERENCES IN END-OF-LIFECARE: HOSPITALIZATIONAND EXPENDITURES A growing body of evidence shows consistent racial differences in the intensity of end-of-life medical care in the United States ( www.jwatch.org /na41774 and www.jwatch.org /na42087 ). Two studies in the September Journal of the American Geriatrics Society provide additional insights. Using several Medicare-related databases, researchers examined end-of-life hospitalization among nearly 400,000 nursing home residents ( http:// dx.doi.org /10.1111/jgs.14284 ). Black residents had a significantly higher rate of hospitalization during the last month of life than did white residents (43% vs . 32%); among a subgroup of patients with severe cognitive impairment, the difference was even more striking (37% vs . 22%). White residents were much more likely than were black residents to have do-not-hospitalize or do-not-resuscitate orders. In a retrospective cohort study ( http:// dx.doi.org /10.1111/jgs.14263 ), researchers analyzed the associations between end-of-life medical expenditures and race or ethnicity for more than 7,000 Medicare decedents; personal information about these patients was collected from interviews with their surviving friends or families. In unadjusted analyses, expenditures during the last 6months of life were significantly higher for black and Hispanic patients than for white patients (about US$52,000 and US$55,000 vs . US$39,000). In models adjusted for clinical, demographic, socioeconomic, and geographic factors and for the existence of advance directives the differences in end-of-life expenditures across racial and ethnic groups were reduced by about half, but not abolished: Significantly higher expenditures persisted for blacks and Hispanics by roughly US$7,000 compared with whites, suggesting that the adjusted-for factors do not adequately explain the difference in expenditures. These researchers speculate that religious beliefs, cultural background, systemic or organizational factors , and patient and provider communication issues might contribute to the unexplained racial differences in end-of-life medical care. Surely these factors are relevant, but they should be considered in a broader historical and sociological context: Conscious or subconscious mistrust between minorities and medical providers could be expressed through insistence on more aggressive medical care near the end of life. NEW BIOLOGIC TREATMENT DRAMATICALLY SHRINKS PLAQUES IN ALZHEIMER DISEASE About 25years ago, β-amyloid was clearly shown to be neurotoxic and likely an important part of the pathogenesis of Alzheimer disease. In mice, therapies that inhibited the production, or sped the degradation, of β-amyloid caused a regression of plaques and improved cognitive function. But results of multiple trials in people, based on the amyloid hypothesis , have been disappointing. In a preclinical mouse study, a new monoclonal antibody called aducanumab was shown to enter the brain, bind selectively to β-amyloid in plaques, and shrink plaques. Those findings prompted a randomized, placebo-controlled trial in 170 patients who had mild cognitive impairment or early Alzheimer disease and positron-emission tomographic (PET) scans positive for β-amyloidcontaining plaques. Intravenous infusions were given every month for a year. Findings appear in the September1 issue of Nature ( http:// dx.doi.org /10.1038/nature19323 ). At the end of treatment, PET scans showed a dramatic resolution of plaques in all of the aducanumab patients. Some, but not all, cognitive studies showed slower cognitive decline in the aducanumab patients than in the placebo patients. This study unequivocally shows that this new monoclonal antibody can dramatically shrink Alzheimer disease plaques. The study did not convincingly show cognitive improvements, but it was underpowered to do so. Larger trials are now underway. An editorialist states ( http:// dx.doi.org /10.1038/537036a ) that if these studies show cognitive benefits, it will provide strong support for the amyloid hypothesis and be a game-changer for the disease. This study was manufacturer-supported. TREATMENT OPTIONS FOR RA AFTERINITIAL ANTI-TNF THERAPY HASFAILED At least a third of patients with rheumatoid arthritis have inadequate responses or adverse reactions to therapy with tumor necrosis factor inhibitors. Its difficult to know which biologic to choose next to treat these patients. In a study in the September20 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2016.13512 ), researchers in France and Monaco randomized 300 patients with rheumatoid arthritis and inadequate responses to initial anti-TNF therapy to either a second anti-TNF agent or another biologic with a different mechanism of action (namely abatacept [trade name: Orencia], rituximab [trade name: Rituxan], or tocilizumab [trade name: Actemra]), that was chosen by the treating clinician. At 6months, 70% of the patients who got non-TNF biologics achieved good or moderate responses, compared with 50% of the patients who got second anti-TNF agents thats a significant difference. The responses were similar across all non-TNF agents. Differences between the two groups persisted and remained significant at a year. Serious adverse events were similar in the two groups. This study implies that a patient with rheumatoid arthritis in whom a first tumor necrosis factor inhibitor fails might benefit from switching to a biologic with a different mechanism of action. But the study wasnt powered to identify differences between individual biologics. Plus, non-TNF agents were given intravenously, whereas second anti-TNF agents were self-administered. Even so, given the lack of guidelines on how to treat these patients, choosing a biologic with a different mechanism of action is appropriate. SIMPLE BLOOD TEST TO DEFINEDISEASE ACTIVITY IN RA WOULD BE A GAME CHANGER With the advent of new, more-potent therapies for patients with rheumatoid arthritis, the treatment goal has become remission or very low disease activity. Many validated clinical diseaseactivity tools are used to monitor rheumatoid arthritis disease activity, but a blood test that could accomplish this monitoring easily and objectively would be welcomed. In the past few years, a blood test (known as Vectra DA) with a simple draw that measures 12 different biomarkers has been touted as defining disease activity. To see whether the results of Vectra DA correlate with standard clinical outcomes, researchers evaluated data from 500 patients with results from Vectra DA and from four standard clinical measures during 2years. Findings appear in the Septemberissue of Arthritis & Rheumatology ( http://doi .org /10.1002/art.39714 ). The patients got either abatacept (trade name: Orencia) or adalimumab (trade name: Humira); all of the patients got methotrexate. At baseline, the Vectra DA results mirrored validated clinical measures of disease activity. But at 3months, 1year, and 2years, there was no association between Vectra DA scores and disease activity. Plus, radiographic progression correlated with standard clinical measures, but Vectra DA scores did not reflect radiographic outcomes. Using a blood test to monitor rheumatoid arthritis disease activity is appealing, but, in this study (and at least for the two biologic drugs abatacept and adalimumab), Vectra DA scores did not correlate with standard clinical outcomes. Plus, this test costs about US$1,000 and is not always covered by insurance. Clinicians need to continue to monitor rheumatoid arthritis disease activity the old-fashioned way by talking with the patient, collecting a history, and performing a physical exam. BIOLOGIC THERAPIES APPEAR TO LOWER SEPSIS RISK IN RA PATIENTS Biologic therapies increase the risk for infection in patients with rheumatoid arthritis. Because tumor necrosis factor is involved in the development of sepsis, tumor necrosis factor inhibitors and interleukin-1 receptor antagonists were first studied in patients with sepsis (rather than as medications for rheumatoid arthritis), but showed little efficacy. Still, in animal models, treatment with these agents before the development of sepsis did improve survival. In an observational study in the September Annals of the Rheumatic Diseases ( http:// dx.doi.org /10.1136/annrheumdis-2015-207838 ), researchers in Germany examined outcomes of serious infections in 12,000 patients with rheumatoid arthritis who were being treated with biologic or conventional disease-modifying antirheumatic drugs. During a follow-up of as long as 10years, 1,000 serious infections were reported (most commonly pneumonia and bone and joint infections), 12% of which progressed to sepsis within a month. The patients with serious infections were older, had a longer duration of rheumatoid arthritis, and had more comorbidities than did the patients without serious infections. The risks for subsequent sepsis and fatal outcomes were significantly lower among the patients taking biologic therapies at the time of serious infection than among the patients taking conventional disease-modifying antirheumatic drugs. This provocative study raises the possibility that, although biologic therapies heighten the risk for infection, they nevertheless might mitigate the complications or severity of infections that do develop in patients who take these drugs. Currently, most rheumatologists stop biologic therapies when serious infection occurs. But when the likely rheumatologic benefit of resuming biologic therapy is thought to outweigh the excess risk for infection during treatment, maybe biologics should be reinstated when the active infection clears, given their apparently favorable effect on the severity of subsequent infections that might occur during their use. GUIDELINE WATCH: TB SCREENING IS WARRANTED IN SOME POPULATIONS Twenty years ago was the last time that the United States Preventive Services Task Force evaluated the utility of screening and treating patients at high risk for latent tuberculosis ( https:// www. ncbi.nlm.nih .gov /books/NBK15486/ ). The changing epidemiology of tuberculosis infection in the United States and new testing and treatment protocols prompted the Task Force to perform a new evidence-based systematic review and issue a recommendation statement, both of which appear in the September6 issue of JAMA ( http:// dx.doi.org /10.1001/jama.2016.10357 and http:// dx.doi.org /10.1001/jama.2016.11046 ). The Task Force found moderate evidence (Grade B) to support TB screening in patients at higher-than-average risk, including those who are foreign born and those living in high-risk congregate settings like homeless shelters or prisons. (Its important to note that the Task Force didnt consider data that pertained to high-risk patients for whom screening is an accepted part of medical care [like patients who are HIV-positive and patients starting immunosuppressive drugs]. Data that support accepted public health protocols [like screening healthcare workers and workers in prisons or shelters] were also not included.) Few harms of screening were identified. Harms consisted mostly of hepatotoxicity from all standard drug regimens that are used for treating patients with TB (namely, isoniazid alone, rifampin alone, and rifapentine [trade name: Priftin] plus isoniazid). Given that up to 10% of the patients with latent TB infections will develop active disease, screening 100,000 high-risk patients should prevent between 50 cases to 150 cases of active TB, at the expense of 7 cases to 70 cases of drug-related hepatotoxicity. The Task Force found both forms of testing skin testing and the new interferon-γrelease assays to be acceptably sensitive and specific. Editorialists enumerate ( http:// dx.doi.org /10.1001/jama.2016.11021 ) some ongoing problems with tuberculosis screening that these guidelines do not address. These problems include a high rate of false-positive screening results in low-prevalence populations (including workers in many healthcare facilities in the United States) and poor completion rates for prophylactic treatment. To improve screening protocols, we need better ways to identify particular individuals with latent TB infections who are most likely to progress to active disease. STOP TREATING ALL PATIENTS WITH FEBRILE NEUTROPENIA SIMILARLY Often, patients undergoing oncologic treatment present to emergency departments with febrile neutropenia; generally, these patients are admitted and given parenteral antibiotics. But guidelines from the Infectious Diseases Society of America ( http:// dx.doi.org /10.1093/cid/cir073 ) and the American Society of Clinical Oncology ( http:// dx.doi.org /10.1200/JCO.2012.45.8661 ) recommend that low-risk patients with febrile neutropenia be discharged from the emergency department with oral antibiotics. To risk-stratify patients, the guidelines recommend the Multinational Association for Supportive Care in Cancer score ( www. mascc .org /mascc-fn-risk-index-score ), which classifies patients as low or high risk based on their burden of disease; blood pressure; age; hydration status; and history of outpatient fever, chronic obstructive pulmonary disease, and fungal infection. In a study on the website of Academic Emergency Medicine ( http:// dx.doi.org /10.1111/acem.13079 ), researchers reviewed the charts of patients with febrile neutropenia without known sources who presented to an emergency department with a large oncology population during a 5-year period. They used the Multinational Association for Supportive Care in Cancer score to risk stratify patients, and then classified each patients care as discordant or concordant with the guidelines. Of 170 patients, a quarter were low risk, and among these low-risk patients, all but two got discordant care. Although some of the low-risk patients were undertreated, 80% were either admitted unnecessarily or given parenteral (rather than oral) antibiotics. None of the low-risk patients died or had sepsis-induced hypotension within 30days. In this study, low-risk patients with febrile neutropenia got overly aggressive treatment that was discordant with contemporary guidelines; presumably, this reflects the tendency of clinicians to perceive bad outcomes following less-intensive treatment as more blameworthy than bad outcomes after overly aggressive treatment. Administering guideline-concordant care for these patients will require the collaboration of clinicians from emergency medicine, oncology, infectious diseases, and primary care. At the time NEJM Journal Watch reviewed this paper, its publisher stated that it was not in its final form and that subsequent changes might be made. POTENTIAL ROLE FOR A COLORECTALCANCER RISKCALCULATOR? A colorectal cancer risk calculator ( www. cancer .gov /colorectalcancerrisk ) from the National Cancer Institute incorporates risk factors namely, sex, current age, body-mass index, vegetable intake, the use of aspirin or nonsteroidal anti-inflammatory drugs, level of exercise, past colorectal cancer screening, smoking history, and estrogen status (in women) in addition to family history. In a study in the September1 issue of Cancer ( http:// dx.doi.org /10.1002/cncr.30096 ), researchers determined whether the NCI calculators predicted 10-year risk for colorectal cancer would correlate with the presence of advanced neoplasia in 500 patients who underwent screening colonoscopy. The definition of advanced neoplasia included tubular adenoma measuring 10mm or larger, villous or tubulovillous adenoma, adenoma with high-grade dysplasia, and several other categories. Among the patients whose calculator-predicted colorectal cancer risk was lowest (a 10-year risk lower than 0.6%), the prevalence of advanced neoplasia on colonoscopy was 6%. In contrast, among those whose predicted colorectal cancer risk was highest (a 10-year risk higher than 1.8%), the prevalence of advanced neoplasia was significantly higher, at 17%. Colorectal cancer screening guidelines distinguish between average risk and above-average risk on the basis of family history only. But the risk for colorectal cancer can be somewhat refined albeit imperfectly by incorporating other demographic, clinical, and lifestyle variables. Because advanced neoplastic polyps are considered to be valid surrogate markers for developing colorectal cancer, the researchers suggest that the National Cancer Institute calculator could be used to aid informed decision-making about colorectal cancer screening. For example, among patients who are initially resistant to screening, higher-risk patients might become more willing to undergo invasive screening (meaning, colonoscopy), whereas lower-risk patients who decline invasive screening might be persuaded to try a less-invasive approach (like stool-based testing). LOCALIZED PROSTATE CANCER: RANDOMIZED COMPARISON OF SURGERY, RADIOTHERAPY, AND ACTIVESURVEILLANCE Over the past four years, radical prostatectomy and watchful waiting in men with localized prostate cancer have been compared in two large randomized trials ( www.jwatch.org /na33729 and www.jwatch.org /jw201207240000002 ). Now, on the website of the New England Journal of Medicine ( http:// dx.doi.org /10.1056/NEJMoa1606220 ), researchers in the United Kingdom report the findings from a three-arm randomized trial in which 1600 men between the ages of 50 and 69 with prostate-specific antigendetected cancer got radical prostatectomy, radiotherapy plus neoadjuvant androgen-deprivation therapy, or active surveillance. At trial entry, the patients average age was 62, their median PSA level was 4.8 ng/ mL, and 80% had a Gleason score of 6. Active surveillance involved PSA testing every 3months to 6months, and a 50% rise in PSA levels during a year triggered a review to reconsider radical therapy. During the trial, half of the active surveillance patients eventually underwent prostatectomy or radiotherapy. During a median follow-up of 10years, there were no significant differences among the three groups in prostate cancerspecific mortality (roughly 1%) or overall mortality (roughly 10%). But the incidence of metastatic disease was significantly higher with active surveillance than with surgery or radiotherapy (6.1% vs . 2.4% and 2.9%). The researchers also tracked patient-reported outcomes using standardized questionnaires ( http:// dx.doi.org /10.1056/NEJMoa1606221 ); they found that: Urinary incontinence was more problematic in the surgery group than in the other two groups. Sexual dysfunction was most common in the surgery group and least common in the surveillance group. Bowel symptoms were more common in the radiotherapy group than in the other two groups. The differences among the groups in urinary, sexual, and bowel symptoms tended to be most evident during the first 1year to 2years and narrowed later on. Overall health-related quality of life was similar in the three groups. Men with localized prostate cancer face difficult treatment decisions; this trials results can help to guide discussions with these patients. Ten-year mortality seems to be unaffected by initial treatment choice, and about 30 men would need initial treatment with surgery or radiotherapy to prevent 1 case of metastatic disease. The estimates of side effects reported in this trial can be shared with patients. But its important to keep in mind that the proportion of men who eventually crossed over from surveillance to radical treatment was quite high and that men in the radiotherapy arm also got neoadjuvant androgen-deprivation therapy. 5 α -REDUCTASE INHIBITORS ARENT ASSOCIATED WITH RISK FOR ERECTILEDYSFUNCTION 5α-reductase inhibitors are used to treat patients with benign prostatic hyperplasia or male pattern baldness (alopecia). But because 5α-reductase inhibitors lower available 5α-dihydrotestosterone, this class of drugs might cause sexual side effects like erectile dysfunction. In a case-control analysis on the website of The BMJ ( http:// dx.doi.org /10.1136/bm j. i4823 ), researchers in the United Kingdom estimated the risk for erectile dysfunction in 70,000 men 40 or older with benign prostatic hyperplasia and 12,000 men between the ages of 18 and 59 with alopecia who did not have baseline sexual dysfunction or conditions that might affect sexual function. In the benign prostatic hyperplasia cohort, the patients got prescriptions for 5α-reductase inhibitors only (namely, finasteride or dutasteride), α-blockers (like tamsulosin) only, or both drugs; in the alopecia cohort, the patients got prescriptions for finasteride or got no treatment. The men who got diagnoses of or treatment for erectile dysfunction (these were the cases) were matched by age, practice site, and other factors with as many as four controls who were not diagnosed with or treated for erectile dysfunction. In the patients with benign prostatic hyperplasia, the use of a 5α-reductase inhibitor (with or without an α-blocker) was not associated with an excess risk for erectile dysfunction compared with the use of an α-blocker only. Notably, the risk for erectile dysfunction increased with a longer duration of benign prostatic hyperplasia, independent of exposure to 5α-reductase inhibitors. In the patients with alopecia, the use of finasteride was also found not to be associated with an excess risk for erectile dysfunction compared with nonuse. In this study, 5α-reductase inhibitors were not associated with an excess risk for erectile dysfunction in men with benign prostatic hyperplasia or alopecia. Because the risk for erectile dysfunction increases with a longer duration of benign prostatic hyperplasia (irrespective of exposure to 5α-reductase inhibitors), the concern about developing erectile dysfunction should not be a reason to forgo effective treatment for benign prostatic hyperplasia.

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Learning Format 6 Hours
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Infectious Diseases Geriatrics Neurology Rheumatology Emergency Medicine Internal Medicine