NEJM Hosts SPRINT Data Analysis Challenge

Posted by • October 24th, 2016

challengeClinical trials are paramount to the advancement of medical knowledge and directly impact patients’ lives. Sharing pivotal data from these trials across the medical profession in a fundamentally transparent way allows for the further advancement of science and maximization of clinical trial participants’ contributions.

In order to demonstrate the potential benefits of clinical trial data sharing, the New England Journal of Medicine is sponsoring the SPRINT Data Analysis Challenge. The SPRINT Challenge tasks you with analyzing the dataset underlying the SPRINT article, A Randomized Trial of Intensive versus Standard Blood-Pressure Control along with any other publicly available dataset, and identifying a novel scientific or clinical result.

The SPRINT Challenge is an opportunity for health care professionals, researchers, and scientists from around the world to shape the future of clinical trial data sharing. Additionally, participants with the best entries may win a prize and present their findings at the Aligning Incentives for Sharing Clinical Trial Data summit and web event on April 3-4, 2017 in Boston, MA.

Visit the SPRINT Challenge website at for more information and official rules.

Chronic Cough

Posted by • October 20th, 2016


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Cough is the most common symptom for which patients seek medical attention. Chronic cough is more common among women than among men, most commonly occurs in the fifth and sixth decades of life, and can persist for years, with substantial physical, social, and psychological effects. Professional guidelines describe systematic approaches to the evaluation and management of chronic cough; these guidelines are based largely on consensus opinion and observational data from the medical literature. The evaluation of chronic cough should address the possibilities of asthma, gastroesophageal reflux disease, and postnasal drip and may require more specialized investigations. For patients with refractory chronic cough, other treatment approaches may be necessary. A new Clinical Practice article explains.

Clinical Pearl

How is chronic cough defined?

Estimates of the prevalence of cough vary, but as much as 12% of the general population report chronic coughing, defined as a cough lasting for more than 8 weeks.

Clinical Pearl

Of the many drugs that may produce cough as a side effect, which drug class is most commonly associated with cough?

Cough is listed as a side effect of many drug treatments but is most commonly associated with the use of angiotensin-converting–enzyme (ACE) inhibitors; cough occurs in approximately 20% of patients treated with ACE inhibitors.

Morning Report Questions

Q: What tests or empiric treatment would be appropriate for a patient with a chronic cough, given the most common etiologies? 

A: In the context of normal results of chest radiography and spirometry, the most common conditions associated with chronic cough are asthma, gastroesophageal reflux disease, and rhinosinusitis, although the prevalence of each of these varies substantially among cough clinics. Although most cases of asthma are associated with abnormalities on routine spirometry, methacholine challenge to assess for bronchial hyperreactivity is indicated for patients who have normal results and no other obvious cause of cough; levels of exhaled nitric oxide may also be elevated. Although data from randomized trials to guide the management of cough-variant asthma are lacking, clinical experience suggests that this condition usually responds to treatment with inhaled glucocorticoids. The relationship between cough and esophageal reflux is complex but is becoming clearer. Guidelines suggest a trial of treatment with acid-suppression therapy — for example, twice-daily treatment with proton-pump inhibitors (PPIs) for up to 3 months — in patients with chronic cough. However, many patients with cough do not have symptomatic gastroesophageal reflux disease, and most randomized, controlled trials of reflux treatment for cough have not shown a significant improvement in association with this type of treatment. Patients with chronic cough often report a sensation of postnasal drip. Guidelines recommend nasal glucocorticoids and antihistamines for patients with allergic rhinitis and chronic cough, but randomized, controlled trials to support this approach are lacking, and clinical experience indicates that the responses to this treatment are often disappointing.

Q: What is the recommended management of patients in whom asthma, rhinosinusitis, and reflux have been ruled out as a cause of cough?


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A: In patients in whom asthma, nasal disease, and reflux have been ruled out (on the basis of diagnostic investigations or trials of treatment), other conditions that may manifest with chronic coughing and could respond to treatment should be considered, and referral should be made to a specialty cough clinic, if one is available. Conditions associated with chronic cough include obstructive sleep apnea, eosinophilic bronchitis, tonsillar enlargement and recurrent tonsillitis, and external ear disease mediated through the auricular branch of the vagus nerve. In cases in which cough remains refractory, high-resolution computed tomographic (CT) scanning of the thorax is recommended to rule out parenchymal lung disease that is not visible on plain chest radiographs (e.g., pulmonary fibrosis, bronchiectasis, or sarcoidosis). Bronchoscopy may be used to identify conditions such as tracheobronchomalacia, chronic bronchitis, and tracheopathia osteochondroplastica, which may be missed on CT scanning.

Graves’ Disease

Posted by • October 20th, 2016


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Graves’ disease is an autoimmune disorder in which the thyroid is activated by antibodies to the thyrotropin receptor. The hyperthyroidism that develops is one of many somatic and psychiatric manifestations of the disease that can affect the quality and length of life. The disease is the most common cause of hyperthyroidism, with an annual incidence of 20 to 50 cases per 100,000 persons. The incidence peaks between 30 and 50 years of age, but people can be affected at any age. The lifetime risk is 3% for women and 0.5% for men. A new Review Article summarizes.

Clinical Pearl

• How common is Graves’ ophthalmopathy?

Orbital imaging reveals subtle abnormalities in 70% of patients with Graves’ disease. In specialized centers, clinically consequential ophthalmopathy is detected in up to 50% of patients with Graves’ disease, and it threatens sight as a consequence of corneal breakdown or optic neuropathy in 3 to 5% of such patients.

Clinical Pearl

• How does patient age influence the clinical manifestations of Graves’ disease?

The manifestations of Graves’ disease depend on the age of the patient at the onset of hyperthyroidism, as well as the severity and the duration of hyperthyroidism. Weight loss, decreased appetite, and cardiac manifestations are more common in elderly persons with hyperthyroidism than in those who are younger. Atrial fibrillation due to hyperthyroidism is rare in patients who are younger than 60 years of age but occurs in more than 10% of patients who are 60 years or older. Palpable goiter develops in most patients with hyperthyroidism who are younger than 60 years of age, as compared with less than 50% of older patients. Severe ophthalmopathy is more likely to develop in older men than in younger persons.

Morning Report Questions

Q: What percentage of patients with Graves’ disease who are treated with methimazole and propylthiouracil have a durable remission? 

A: Methimazole, carbimazole (which is converted to methimazole and is not available in the United States), and propylthiouracil inhibit thyroid peroxidase and thus block thyroid hormone synthesis. Propylthiouracil also blocks extrathyroidal deiodination of thyroxine to triiodothyronine. Both methimazole and propylthiouracil are associated with a high risk of recurrence after treatment has been withdrawn. Durable remission occurs in 40 to 50% of patients. Repeated therapy carries an even lower likelihood of success.

Q: How does thyroid-associated ophthalmopathy present, and how is it treated?

A: Hyperthyroidism and ophthalmopathy typically occur within 1 year of each other but can be separated by decades. Disease development is heralded by an active phase lasting up to 3 years and dominated by evolving symptoms and signs of inflammation and congestion. Proptosis, eyelid swelling, and diplopia may prompt initial medical attention. Some patients have dry eye, increased tearing, and ocular discomfort early in the active phase. This is followed by an inactive phase in which the ocular manifestations become stable. In a cohort of consecutively assessed patients with Graves’ disease, the prevalence of distinct abnormalities was as follows: eyelid retraction, 92%; exophthalmos, 62%; extraocular muscle dysfunction, 43%; ocular pain, 30%; increased lacrimation, 23%; and optic neuropathy, 6%. Treatment for ophthalmopathy depends on the phase and severity of the disease. The majority of patients require only conservative measures. These include enhancement of tear-film quality and maintenance of ocular surface moisture. Patients with disease that is severely symptomatic and sight-threatening may benefit from intravenously administered pulse glucocorticoid therapy, which appears to have a more favorable side-effect profile than glucocorticoids administered orally, although pulse therapy is not without risks. Glucocorticoids are frequently effective in reducing inflammatory symptoms, but most experts do not believe that they modify the course of the disease. Orbital decompression surgery during active disease is usually reserved for patients in whom compressive optic neuropathy has developed or is imminent.


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Romosozumab Treatment in Postmenopausal Women with Osteoporosis

Posted by • October 19th, 2016


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You are seeing one of your patients, a vivacious and active 60-year-old woman who works full time. She underwent bone densitometry testing, and the results show a T score of -2.7 at the femoral neck. Further, a short sentence on the report confirms a diagnosis of osteoporosis. Knowing that osteoporosis can lead to both vertebral and nonvertebral fractures that can affect quality of life and increase mortality risk, you must decide what to recommend.

Treatment of osteoporosis prevents further deterioration of bone mineral density. Although effective options are available, patients and physicians are often concerned about the side effects of bisphosphonates, which are antiresorptive agents, and have been approved for treatment of osteoporosis for more than a decade. Another type of medication, denosumab, a monoclonal antibody that inhibits osteoclast activation, has been shown to reduce vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis. Denosumab was the first biologic therapy approved for osteoporosis treatment, but reservations exist about its widespread use because, as with bisphosphonates, osteonecrosis of the jaw and atypical femoral fractures have been reported. Yet another type of agent is now available, a monoclonal antibody developed to target and inhibit sclerostin, a protein synthesized by osteoclasts that negatively affects bone formation.

In this week’s issue of NEJM, Cosman and colleagues report the results of a phase 3, international, randomized, placebo-controlled trial that examined the effect of romosozumab on fracture risk. The investigators randomized 7180 ambulatory post-menopausal women, aged 55–90 years with T-scores of -2.5 to -3.5 at the total hip or femoral neck, to receive subcutaneous injections of romosozumab or placebo once monthly for 12 months. Most participants were recruited from Central and Latin America. Patients, investigators, and sponsors were blinded during the initial 12-month phase of the trial; during a follow-on phase, all participants received open-label subcutaneous injections of denosumab every 6 months for an additional 12 months. Thoracic and lumbar spine radiographs were obtained every 6 months during both phases of the study. The coprimary endpoints were the incidences of new vertebral fracture at 12 and 24 months.

During the first 12 months, the incidence of new vertebral fractures among the 3589 romosozumab recipients was 0.5%, compared to 1.8% among the 3591 placebo recipients, representing a relative decrease of 73% with romosozumab (risk ratio, 0.27; 95% CI, 0.16 to 0.47; P<0.001). During the same period, the relative decrease in the number of clinical fractures in the romosozumab group compared to placebo was 36% (P=0.008); however, a 25% relative decrease in nonvertebral fractures between groups was not significant (P=0.096). At 24 months, after the two groups transitioned to denosumab, the relative decrease in vertebral fractures among those treated with romosozumab remained significant at 75% (risk ratio, 0.25; 95% CI 0.16 – 0.40; P<0.001).

Rates of adverse events, such as arthralgia and cardiovascular events, were similar in the two groups; however, in the romosozumab group, seven cases of hypersensitivity were reported in the first year, as well as one atypical femoral fracture and two cases of osteonecrosis of the jaw (one during the first year and the other after one dose of denosumab).

Although romosozumab was associated with a reported relative decrease in the incidence of vertebral fractures, it is unclear whether bone biologists and clinicians will be satisfied with these outcomes. The editorialists, Dr. Clifford Rosen and Dr. Julie Ingelfinger, noted the “relatively rapid progress from discovery of sclerostin (1999) to the completion of a phase 3 trial (2016) with a sclerostin antibody” but raised concerns about romosozumab’s potentially limiting adverse events. Other factors to consider when considering biologic therapy for osteoporosis and other conditions include cost, access, and efficacy.

A Man with Diplopia and Polyuria

Posted by • October 13th, 2016


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The histologic diagnosis of IgG4-related disease is predicated on the presence of characteristic histologic features, which include the presence of a dense lymphoplasmacytic infiltrate accompanied by storiform fibrosis (fibrosis with a whorled or starlike pattern that resembles a woven mat), obliterative phlebitis, or both. Another essential component of the diagnostic algorithm is the presence of increased numbers of IgG4-positive plasma cells, as well as an elevated IgG4:IgG ratio. A 53-year-old man was seen in outpatient clinics of a hospital because of a 1-year history of diplopia, polydipsia, and polyuria. Imaging studies showed mucosal thickening of the sphenoid sinus and enlargement of the pituitary gland. A diagnostic procedure was performed in a new Case Record.

Clinical Pearl

Are serum IgG4 concentrations always elevated in IgG4-related disease?

Although many patients with IgG4-related disease have a substantially elevated serum IgG4 concentration, a 2015 study of histopathologically confirmed cases of IgG4-related disease showed that 45% of the patients had normal serum IgG4 concentrations before they received treatment.

Clinical Pearl

What are some of the findings in peripheral blood and tissues in patients with active IgG4-related disease?

Patients with active IgG4-related disease typically have large clonal expansions of CD4+ cytotoxic T lymphocytes in the peripheral blood that express perforin and granzymes and that secrete profibrotic cytokines. These clonally expanded CD4+ cytotoxic T lymphocytes are the dominant T cells in the immune infiltrate in affected tissues. Activated CD19+CD20−CD38highCD27high B cells (called plasmablasts) are also a dominant feature in the blood and tissues of patients with active IgG4-related disease.


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Morning Report Questions

Q: Compare and contrast IgG4-related disease with granulomatosis with polyangiitis.

A: Differentiating between these two conditions is exceptionally difficult in some cases. High concentrations of IgG4-positive plasma cells have been reported in patients with granulomatosis with polyangiitis, as well as in patients with other conditions, a finding that precludes reliance on immunostaining for IgG4 to diagnose IgG4-related disease. Fibrosis, which may occasionally be storiform, is not uncommon in patients with granulomatosis with polyangiitis. In fact, there is substantial overlap between the histologic and immunohistochemical features of the two diseases, and it is conceivable that before IgG4-related disease was recognized as a discrete disease, cases of IgG4-related disease may have been misclassified as granulomatosis with polyangiitis. IgG4-related disease is less likely than granulomatosis with polyangiitis to lead to erosive sinonasal disease, but cases of IgG4-related disease that led to facial-bone erosion have been described.

Q: What is the treatment for IgG4-related disease?

A: Treatment with glucocorticoids is an effective initial therapy for most patients with IgG4-related disease. Unfortunately, many patients require a prolonged course of glucocorticoids to maintain remission, and a substantial number of patients have disease flares despite ongoing therapy. Because IgG4-related disease is characterized not only by elevated serum IgG4 concentrations in many patients but also by increased numbers of circulating cells that are characterized as plasmablasts (i.e., IgG4+ and total plasmablasts), treatment strategies that target cells of the B-lymphocyte lineage are being investigated. Preliminary evidence indicates that B-cell depletion therapy is an effective treatment strategy in patients with IgG4-related disease.

Ten-Year Follow-up in the ProtecT Trial

Posted by • October 13th, 2016


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The management of clinically localized prostate cancer that is detected on the basis of prostate-specific antigen (PSA) levels remains controversial. The National Institute for Health Research–supported Prostate Testing for Cancer and Treatment (ProtecT) trial was designed to evaluate the effectiveness of the three major contemporary treatment approaches to reducing prostate-cancer mortality and improving clinical outcomes in men with PSA-detected clinically localized disease. Hamdy et al. reported the effectiveness of each intervention in relation to prostate-cancer–specific mortality and all-cause mortality and the incidence of metastases and disease progression at a median of 10 years of follow-up in the randomized trial. In the ProtecT trial, over 1600 men with PSA-detected localized prostate cancer were assigned to active monitoring, prostatectomy, or radiotherapy. Although more patients assigned to active monitoring had disease progression, overall survival was similar in the three groups in a new Original Article.

Clinical Pearl

• Why is the management of clinically localized prostate cancer that has been detected with PSA testing controversial?

In the United States alone, an estimated 180,890 cases will be diagnosed in 2016, and 26,120 men will die from the disease. The widespread use of PSA testing has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer, but many men do not benefit from intervention because the disease is either indolent or disseminated at diagnosis. Prostate cancer often progresses slowly, and many men die of competing causes. In addition, interventions for prostate cancer can have adverse effects on sexual, urinary, or bowel function.

Clinical Pearl

Are there prostate-cancer mortality differences between prostatectomy, radiotherapy, and active monitoring in men with PSA-detected clinically localized disease?

At a median follow-up of 10 years, the ProtecT trial showed that mortality from prostate cancer was low, irrespective of treatment assignment. Prostate-cancer–specific survival was at least 98.8% in all groups, and there was no significant difference among the three randomized groups (P=0.48 by log-rank test). There was no evidence that between-group differences in prostate-cancer mortality varied according to age, PSA level, Gleason score, or clinical stage.

Morning Report Questions

Q: How do prostatectomy, radiotherapy, and active monitoring compare regarding disease progression and all-cause mortality in men with PSA-detected clinically localized disease?

A: In the trial by Hamdy et al., the incidence of disease progression was higher in the active-monitoring group than in the surgery and radiotherapy groups (112 men in the active-monitoring group, 46 in the surgery group, and 46 in the radiotherapy group; P<0.001 for the overall comparison). Deaths from any cause were evenly distributed across the treatment groups (P=0.87 by likelihood-ratio test), although the confidence intervals for the hazard ratios were wide and so did not provide strong evidence of equivalence across the groups.

Q: What are some of the limitations of the ProtecT trial?

A: There are several limitations of the ProtecT trial. First, the protocol was developed almost two decades ago; since then, treatments and diagnostic techniques for prostate cancer have evolved. The ProtecT trial did not use multiparametric magnetic resonance imaging to evaluate patients at diagnosis or during monitoring. Surgical techniques have changed with robot-assisted laparoscopic prostatectomy, and although all patients in the radiotherapy group received neoadjuvant androgen-deprivation therapy with three-dimensional conformal irradiation, new techniques such as intensity-modulated radiotherapy have been introduced, and brachytherapy was not included. Second, less than 1% of the participants enrolled in this trial were of African–Caribbean ancestry, but this percentage reflected the population in the recruiting centers who were in the trial age range.

Breast Cancer Tumor Size, Mammography, and Screening Effectiveness

Posted by • October 12th, 2016


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A good screening test is capable of identifying a precursor or early-stage disease in an asymptomatic patient and targets a disease for which early treatment is available to improve the patient’s ultimate outcome. Controversies about mammography screening guidelines for early detection of breast cancer include the appropriate age to start and stop screening, the frequency of testing, and how to manage and notify patients with dense breasts. These controversies stem from the need to balance the benefits of early detection (with the aim of reducing breast-cancer mortality) against the costs of screening (including the cost of the test as well as the financial and emotional costs of follow-up testing such as biopsies, repeat imaging, and potential harms of overdiagnosis).

In a paper entitled “Breast-Cancer Tumor Size, Mammography, and Screening Effectiveness” in this week’s NEJM, investigators from Dartmouth Medical School and the National Cancer Institute aimed to assess the real-world effectiveness of mammography and prevalence of overdiagnosis of breast cancers in the United States. Using data from the large Surveillance, Epidemiology and End Results (SEER) database, the investigators calculated the size distribution and size-specific incidence of breast cancer among women age 40 and older. They then compared size-specific cancer case fatality rates from the era before widespread screening (1975–1979) to rates from the most recent data with 10 years of available follow-up (2000–2002).

The authors hypothesized that an effective screening program would reduce the number of large cancers detected and proportionally increase in the number of small cancers detected, implying that screening identified cancers earlier, while at a smaller size. They found that screening did increase the proportion of small breast cancers (<2 cm) detected from 36% to 68% and decreased the proportion of larger tumors (≥2 cm) detected from 64% to 32%. The incidence of larger tumors decreased by 30 cases per 100,000 women, while the incidence of smaller tumors increased by 162 per 100,000, resulting in a rate of overdiagnosis of 132 per 100,000 (representing small cancers that were not likely to progress to larger cancers).

Using the size-specific case-fatality rates of the larger cancers to estimate mortality reduction, the authors concluded that improvements in breast cancer treatment are responsible for at least two thirds (68%) of the reduction in mortality over time, while screening is responsible for the remainder. The authors acknowledge that tumor biology and genetics are more important than size, and that size is only an imperfect proxy for disease and prognosis. One possible explanation for the relatively small contribution of screening to improved survival is that many small cancers detected by screening have favorable biology, with slow growth and good response to therapy, and therefore prognosis may not be improved by earlier detection. A limitation of the study is that the authors had to assume that the disease incidence was stable over time because true breast cancer incidence is unknown. Although that assumption seems likely to be true, it has not been confirmed.

In an accompanying editorial, Dr. Joann Elmore from the Department of Medicine at the University of Washington cautions that the authors, “rely on data with extensive missing values, make assumptions about underlying disease burden that cannot be verified, and acknowledge that their estimates are imprecise.” However, she concludes that we all must agree that overdiagnosis exists, even if our estimates of its magnitude are not accurate. She adds, “One way to reduce overdiagnosis is targeted, precision screening of persons who have a higher risk of breast cancer rather than screening large populations in which the majority of persons are at a lower risk for harmful disease.”

Dr. Dan Longo, NEJM Deputy Editor adds, “It would seem that the main way forward to resolve the debates on the usefulness of screening mammography is the development of better methods of predicting the biology of mammogram-detected cancers, probably through genetic analysis.”

This study concludes that current population-based mammography screening guidelines result in overdiagnosis of cancers unlikely to affect the life span, and that the mortality reduction gained from improved breast cancer treatments is likely greater than the mortality reduction from screening. These data will help inform efforts to improve the effectiveness of screening programs to maximize the benefits and minimize harms.

Daratumumab for Myeloma

Posted by • October 6th, 2016


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The incorporation of proteasome inhibitors and immunomodulatory drugs into the standard of care has improved outcomes in patients with multiple myeloma over the past 10 years, but most patients still eventually have a relapse. In the October 6, 2016, issue of the New England Journal of Medicine, Dimopoulos et al. report the results of a prespecified interim analysis of a phase 3 trial of daratumumab, lenalidomide, and dexamethasone in patients with relapsed or refractory myeloma. The addition of daratumumab to lenalidomide and dexamethasone resulted in superior response rate and progression-free survival, as compared with lenalidomide and dexamethasone alone, at a cost of more frequent neutropenia and infusion reactions.

Clinical Pearl

What is daratumumab?

Daratumumab, a human IgGκ monoclonal antibody that targets CD38, has shown substantial single-agent efficacy and a manageable safety profile in phase 1–2 studies involving patients with heavily pretreated relapsed or refractory multiple myeloma, with reported overall response rates of 29% and 36%. On the basis of these findings, daratumumab monotherapy (at a dose of 16 mg per kilogram of body weight) was approved by the Food and Drug Administration and the European Medicines Agency for these patients.

Clinical Pearl

• What are the mechanisms of action of daratumumab?

The mechanisms of action of daratumumab comprise immune-mediated effects, including complement-dependent and antibody-dependent cell-mediated cytotoxic effects, antibody-dependent cellular phagocytosis, and apoptosis by means of cross-linking. Moreover, daratumumab may have a role in immunomodulation by means of depletion of CD38-positive regulator immune suppressor cells, which leads to a greater clonal expansion of T cells in patients who have a response than in those who do not.

Morning Report Questions

Q: Does the addition of daratumumab to lenalidomide and dexamethasone improve progression-free survival in patients with relapsed or refractory myeloma?

A: In the study by Dimopoulos et al., the primary end point was progression-free survival. The results showed that the addition of daratumumab to lenalidomide and dexamethasone significantly prolonged progression-free survival and was associated with a 63% lower risk of disease progression or death than lenalidomide and dexamethasone alone among patients with multiple myeloma who had received one or more lines of therapy previously. The treatment effect of daratumumab was consistent regardless of previous exposure to lenalidomide (a limitation being the relatively small number of patients with previous exposure to lenalidomide) and across all subgroups, including patients 65 years of age or older, those with disease that was refractory to proteasome inhibitors or the most recent line of therapy, those with International Staging System stage III disease, and those with previous exposure to a proteasome inhibitor or immunomodulatory drug. The treatment benefit that was associated with daratumumab was also similar in patients with one previous line of therapy and in those with one, two, or three previous lines of therapy.

Q: What were some of the notable adverse events associated with daratumumab in the study by Dimopoulos et al.?

A: In the study by Dimopoulos et al., the most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2.

The Health Effects of Electronic Cigarettes

Posted by • October 6th, 2016


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Although the sale of e-cigarettes is prohibited in some countries, it is legal in most, including the United States, where the FDA recently finalized rules for the regulation of e-cigarettes as a tobacco product. The U.S. market for e-cigarettes is now estimated to be worth $1.5 billion, a number that is projected to grow by 24.2% per year through 2018. Global sales are predicted to reach $10 billion by 2017. The use of electronic cigarettes is growing, and some hope that they will replace what is felt to be the more dangerous nicotine-delivery system — cigarettes. However, data on the long-term safety of e-cigarettes are still being gathered and expanded upon in a new Review Article.

Clinical Pearl

What are the components of an electronic cigarette?

E-cigarettes, also known as electronic nicotine-delivery systems, are devices that produce an aerosol by heating a liquid that contains a solvent (vegetable glycerin, propylene glycol, or a mixture of these), one or more flavorings, and nicotine, although the nicotine may be omitted. The evaporation of the liquid at the heating element is followed by rapid cooling to form an aerosol. E-cigarette aerosol is directly inhaled (or “vaped”) by the user through a mouthpiece. Each device includes a battery, a reservoir that contains the liquid, and a vaporization chamber with heating element. The composition of the aerosol that is generated depends on the ingredients of the liquid, the electric characteristics of the heating element, the temperature reached, and the characteristics of the wick. The constituents of the aerosol generated by e-cigarettes and inhaled by the user are more directly relevant to health than the ingredients of e-cigarette liquids.


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Clinical Pearl

Who is using e-cigarettes?

In 2010, a total of 1.8% of U.S. adults reported having used an e-cigarette at some time, a rate that rose to 13.0% by 2013; reports of “current use” increased from 0.3% to 6.8% during this period. Although tobacco smokers were among those most likely to be current users of e-cigarettes, a third of current e-cigarette users had never smoked tobacco or were former tobacco smokers. Of particular concern regarding public health has been the increasing experimentation with and use of e-cigarettes among persons younger than 18 years of age.

Morning Report Questions

Q: Do e-cigarettes help tobacco smokers quit smoking?

A: The efficacy of e-cigarettes as a smoking-cessation intervention remains uncertain owing to the limited data available from randomized trials. Furthermore, it is difficult to extrapolate the results of studies that used first-generation e-cigarettes to second- and third-generation devices that are more satisfying to users because of changes in aerosol characteristics, nicotine delivery, and the variety of flavors. Recent meta-analyses that have combined data from randomized trials and observational cohort studies have not shed further light on the efficacy of e-cigarettes as a smoking-cessation aid.

Q: Are the flavorings that are added to e-cigarette liquid considered harmless?

A: In 2014, there were an estimated 466 brands and 7764 unique flavors of e-cigarette products; this heterogeneity complicates research on potential health effects. Although some studies suggest that smoking e-cigarettes may be less dangerous than smoking conventional cigarettes, more needs to be learned. A particular challenge in this regard is the striking diversity of the flavorings in e-cigarette liquids, since the effects on health of the aerosol constituents produced by these flavorings are unknown. Many of the liquid flavorings in e-cigarettes are aldehydes, which in some cases are present in concentrations sufficient to pose risks owing to the irritant characteristics of these compounds. Sweet-flavored e-cigarette liquids often contain diacetyl, acetyl propionyl, or both. These flavorings are approved for use in foods but have been associated with respiratory disease when inhaled during manufacturing processes. Some e-cigarette liquids are flavored with tobacco extracts, and these may contain tobacco-specific nitrosamines, nitrates, and phenol, although in far lower concentrations than those found in tobacco products.

Learning More About Living Longer After Myocardial Infarction

Posted by • October 5th, 2016


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To practice medicine is often to be inundated in metrics. Institutions may spend immense resources collecting data on readmission rates, time to treatment, and adherence to therapy. We know that appropriate measurement is key to health care improvement, improved rankings, and reimbursement. However, for many of these metrics, the connection between short-term performance and long-term patient outcomes remains unproven. This may prompt the overwhelmed and pragmatic provider to ask, “Have we even picked the right metric?In this week’s NEJM, Bucholz et al. share results that may help answer this question in patients with acute myocardial infarction (AMI).

The investigators utilized data from the Cooperative Cardiovascular Project (CCP) to assess Medicare hospitalizations for AMI between February 1994 and July 1995. For each hospital involved, they calculated a risk-standardized 30-day mortality rate, and then divided all hospitals into quintiles based on their 30-day mortality performance. Hospitals with the highest mortality rates were categorized as “lowest-performing” and those with the lowest mortality rates were categorized as “highest-performing.” Then, using Medicare enrollment data from 1994 to 2012, the authors identified dates of death for patients included in the initial CCP database, allowing them to estimate life expectancy for each of the hospital quintiles.

Analysis of this data indicated that AMI patients admitted to the lowest-performing 30-day mortality hospitals had the lowest 17-year life expectancy, whereas AMI patients admitted to highest-performing 30-day mortality hospitals had the highest estimated life expectancy. After adjusting for patient-specific factors and hospital-specific clinical factors, AMI patients treated at high-performing hospitals lived on average 0.74 to 1.14 years longer than patients treated at low-performing hospitals. This difference in life expectancy remained statistically significant even when accounting for a hospital’s case mix.

What impact should these findings have on our AMI practice? The results suggest that early, better care resulting in improved short-term mortality may actually create a persistent benefit to patients. They also reinforce the importance of 30-day mortality in assessing the quality and impact of AMI care being administered at our hospitals.

Unfortunately, Bucholz et al. cannot provide us with recommendations on specific interventions or processes in which to invest resources to improve AMI 30-day mortality. In fact, the authors note, prior research has yet to consistently demonstrate a tight link between specific AMI process measurements and AMI patient outcomes, and in their own analysis, adjustment for treatment variables such as use of aspirin and beta-blockers did not fully account for the observed differences in outcome.

Moving forward, these results are an excellent starting point for the next phase of quality improvement in cardiac care. We should continue to critically assess the utility of current metrics, building on those that create value (such as 30-day mortality) and eliminating those that only add to paperwork without providing benefit to patients. As the authors suggest, future AMI improvement efforts could also focus on areas we are less adept at measuring: hospital culture, organizational structure, and collaboration. Regulators, administrators, and front-line providers should begin to think critically about how to leverage this information to improve patient care.

What are you and/or your institution doing to improve care for acute myocardial infarction? When you assess the quality of care you are providing, what metrics are most/least important to you?