NEJM This Week — 2010-12-23

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Welcome to the New England Journal of Medicine Weekly Audio Summary for December 23, 2010. I’m Dr. Michael Bearer. This week’s issue featured on apixaban for thromboprophylaxis after hip replacement, rivaroxaban for venous thromboembolism, imatinib plus peginterferon alfa-2a in chronic myeloid leukemia, long-term mortality in childhood-onset epilepsy, and measuring hospital-wide mortality; a review article on glycemic control in the ICU; a case report of a woman with nausea, jaundice, and pruritus; and Perspective articles on value in health care, on putting the value framework to work, and on protecting global health workers from harm.

Apixaban versus Enoxaparin for Thromboprophylaxis after Hip Replacement

By Michael Rud Lassen, from the Hørsholm Hospital, Denmark

There are various regimens for thromboprophylaxis after hip replacement. Low-molecular-weight heparins such as enoxaparin predominantly inhibit factor Xa but also inhibit thrombin to some degree. Orally active, specific factor Xa inhibitors such as apixaban may provide effective thromboprophylaxis with a lower risk of bleeding and improved ease of use. In this study, patients undergoing total hip replacement were randomly assigned to receive apixaban or enoxaparin. The primary efficacy outcome, which was the composite of asymptomatic or symptomatic deep-vein thrombosis, nonfatal pulmonary embolism, or death from any cause, occurred in 1.4% of patients in the apixaban group (and in 3.9% of patients in the enoxaparin group. The composite outcome of major and clinically relevant nonmajor bleeding occurred in4.8% of patients assigned to apixaban and 5.0% assigned to enoxaparin. Among patients undergoing hip replacement, thromboprophylaxis with apixaban, as compared with enoxaparin, was associated with lower rates of venous thromboembolism, without increased bleeding.

Oral Rivaroxaban for Symptomatic Venous Thromboembolism

By The EINSTEIN Investigators

Rivaroxaban, an oral factor Xa inhibitor, was compared with enoxaparin followed by a vitamin K antagonist for the treatment of acute deep-vein thrombosis (DVT). Rivaroxaban had noninferior efficacy with respect to the primary outcome of recurrent venous thromboembolism (36 events vs. 51 events with enoxaparin–vitamin K antagonist). Major bleeding or clinically relevant nonmajor bleeding occurred in 8.1% of the patients in each group. In the continued-treatment study, rivaroxaban had superior efficacy (8 events vs. 42 with placebo). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11). Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation.

In the editorial, Elaine M. Hylek, from Boston University School of Medicine, writes out that: ‘Alternatives to warfarin have been long awaited. The oral factor Xa inhibitors show great promise. The reversibility of the drugs’ effects and the ability to measure the anticoagulant effect in specific situations will continue to be highly desirable features and will do allay physicians’ concerns. If these novel, breakthrough, oral anticoagulant drugs prove to be effective across the broad spectrum of patients in routine care and are conscientiously priced, the worldwide impact will be huge.’

Imatinib plus Peginterferon Alfa-2a in Chronic Myeloid Leukemia

By Claude Preudhomme, from Centre Hospitalier Universitaire (CHU) de Lille, France

Imatinib (400 mg daily) is considered the best initial therapy for patients with newly diagnosed chronic myeloid leukemia (CML) in the chronic phase. However, only a minority of patients treated with imatinib have a complete molecular remission. This trial was conducted to determine whether administering higher doses of imatinib or combining imatinib with peginterferon alfa-2a or cytarabine would result in higher rates of molecular responses. At 12 months, the rates of cytogenetic response were similar among the four groups. The rate of a superior molecular response was significantly higher among patients receiving imatinib and peginterferon alfa-2a (30%) than among patients receiving imatinib alone (14%). The rate was significantly higher among patients treated for more than 12 months than among those treated for 12 months or less. Gastrointestinal events were more frequent among patients receiving cytarabine, whereas rash and depression were more frequent among patients receiving peginterferon alfa-2a. As compared with other treatments, the addition of peginterferon alfa-2a to imatinib therapy resulted in significantly higher rates of molecular response in patients with chronic-phase CML.

Long-Term Mortality in Childhood-Onset Epilepsy

By Matti Sillanpää, from the Turku University Hospital, Finland

The author reported on long-term mortality in a Finnish cohort of subjects with a diagnosis of epilepsy in childhood. Sixty subjects died (24%); this rate is three times as high as the expected age- and sex-adjusted mortality in the general population. The subjects who died included 48% of subjects who were not in 5-year terminal remission (i.e., seizure-free at the time of death or last follow-up). A remote symptomatic cause of epilepsy (i.e., a major neurologic impairment or insult) was also associated with an increased risk of death as compared with an idiopathic or cryptogenic cause (37% vs. 12%). Of the 60 deaths, 55% were related to epilepsy, including sudden, unexplained death in 18 subjects, definite or probable seizure in 9, and accidental drowning in 6. The deaths that were not related to epilepsy occurred primarily in subjects with remote symptomatic epilepsy. The cumulative risk of sudden, unexplained death was 7% at 40 years overall and 12% in an analysis that was limited to subjects who were not in long-term remission and not receiving medication. Among subjects with idiopathic or cryptogenic epilepsy, there were no sudden, unexplained deaths in subjects younger than 14 years of age. Childhood-onset epilepsy was associated with a substantial risk of epilepsy-related death, including sudden, unexplained death. The risk was especially high among children who were not in remission.

Variability in the Measurement of Hospital-wide Mortality Rates

By David M. Shahian, from Massachusetts General Hospital, Boston

Several countries use hospital-wide mortality rates to evaluate the quality of hospital care, although the usefulness of this metric has been questioned. Massachusetts policymakers recently requested an assessment of 4 common metrics to calculate this aggregate mortality metric for use as a measure of hospital quality. This study found that proportions of discharges that were included by each method ranged from 28% to 95%, and the severity of patients’ diagnoses varied widely. Because of their discharge-selection criteria, two methods calculated in-hospital mortality rates (4.0% and 5.9%) that were twice the state average (2.1%). Pairwise associations of discharge-level predicted mortality probabilities ranged from 0.46 to 0.70. Hospital-performance categorizations varied substantially and were sometimes completely discordant. In 2006, a total of 12 of 28 hospitals that had higher-than-expected hospital-wide mortality when classified by one method had lower-than-expected mortality when classified by one or more of the other methods. Four common methods for calculating hospital-wide mortality produced substantially different results. This may have resulted from a lack of standardized national eligibility and exclusion criteria, different statistical methods, or fundamental flaws in the hypothesized association between hospital-wide mortality and quality of care.

Glycemic Control in the ICU

By Brian P. Kavanagh, from the Hospital for Sick Children, Toronto, Canada

Stress hyperglycemia is the elevation of blood glucose in the presence of acute illness. Factors contributing to hyperglycemia in critical illness include the release of stress hormones (e.g., epinephrine and cortisol), the use of medications such as exogenous glucocorticoids and catecholamines, and the release of mediators in cases of sepsis or surgical trauma, all of which inhibit insulin release and action, thereby enhancing gluconeogenesis, inhibiting glycogen synthesis, and impairing insulin-mediated glucose uptake by tissues. Intravenous dextrose, commonly used in parenteral nutrition and antibiotic solutions, also contributes to hyperglycemia. Hyperglycemia in the ICU has not consistently been shown to portend a worse prognosis in patients with preexisting diabetes. Conversely, hyperglycemia has been linked with worse outcomes in patients not known to have diabetes who are admitted to the ICU and specifically in those with an acute coronary syndrome or stroke. Often, this association reflects the severity of the illness, but hyperglycemia itself may also contribute to the burden of disease. Observational data indicate that for glucose values in the range of 79 to 200 mg per deciliter, the duration of exposure to higher glucose concentrations is inversely associated with survival. Several mechanisms have been hypothesized to explain how hyperglycemia may cause harm However, there are insufficient data to determine the threshold at which an elevated glucose concentration has deleterious effects on tissue. An audio version of this article is available in NEJM.org.

A 19-Year-Old Woman with Nausea, Jaundice, and Pruritus

A CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL, by Lawrence S. Friedman

A 19-year-old woman was in because of nausea, jaundice, and pruritus. 2.5 weeks earlier, malaise, vomiting, and upper respiratory symptoms developed. which resolved after 3 days. Approximately 1 week before admission, pruritus and dark urine developed. Three days before admission, her mother brought her to the emergency department at another hospital because of increasing discoloration of her eyes and skin. The patient was 3 month’s postpartum. Examinations reviewed no spider angiomas, palmar erythema, or telangiectasias, abdominal tenderness, distention, or organomegaly. Bilirubin and aminotransferase levels was elevated. The presentation is one of acute hepatitis, with characteristic clinical and biochemical features, and the differential diagnosis is straightforward. Acute hepatitis is often caused by one of several hepatotropic viruses, by systemic viral infections that may involve the liver, or by drugs or toxic agents, and these must be ruled out in this case.

What Is Value in Health Care?

A perspective article by Michael E. Porter, from Harvard Business School, Boston.

Achieving high value for patients must become the overarching goal of health care delivery, with value defined as the health outcomes achieved per dollar spent. Value should always be defined around the customer, and in a well-functioning health care system, the creation of value for patients should determine the rewards for all other actors in the system. The only way to accurately measure value, then, is to track patient outcomes and costs longitudinally. The outcomes for any medical condition can be arrayed in a three-tiered hierarchy. Tier 1 is the health status that is achieved or, for patients with some degenerative conditions, retained. Tier 2 outcomes are related to the recovery process. Tier 3 is the sustainability of health. Each medical condition (or population of primary care patients) will have its own outcome measures. Measurement efforts should begin with at least one outcome dimension at each tier, and ideally one at each level. Aligning reimbursement with value in this way rewards providers for efficiency in achieving good outcomes while creating accountability for substandard care.

Putting the Value Framework to Work

A perspective article by Thomas H. Lee, from Partners Healthcare System, Boston.

“Value” is a word that has long aroused skepticism among physicians, who suspect it of being code for “cost reduction.” Nevertheless, an increasing number of health care delivery organizations, now describe enhancement of value for patients as a fundamental goal and are using concepts developed by Michael Porter to shape their strategies. The “bad news” is that Making progress in the value framework requires real teamwork, which sometimes seems an unnatural act in health care. It means capturing data in different parts of the delivery system, which means that we all have to use the exact same terminology. And it means sharing accountability for performance. The “good news” is that difficult though they may be, these changes feel like the right thing to do. To improve outcomes and efficiency for patients with specific conditions, providers must organize interdisciplinary teams around those conditions. Nothing can be considered guaranteed about the future for physicians and other health care providers except that there will always be patients who need care. In these uncertain times, health care providers need a path forward. The value framework provides one.

Courting Danger while Doing Good — Protecting Global Health Workers from Harm

A perspective article by Claire Panosian, from the David Geffen School of Medicine, Los Angeles

Until the morning of February 26, 2010, the name Eddie Roach meant nothing to Dr. Panosian, Then a desperate e-mail brought the 32-year-old self-described “global health missionary” into her life. Weeks earlier, Roach had been distributing handheld water purifiers in rural Uganda; now, he was in a Nevada intensive care unit awaiting dialysis and exchange transfusion. Diagnosis? Severe and complicated Plasmodium falciparum malaria. Today, if he could turn back the clock, Eddie Roach would faithfully down antimalarial pills in Uganda. But when he began his trip, Roach’s knowledge about malaria was sketchy, and he feared possible side effects from preventive medication, and he was focused on saving other people’s lives, not protecting his own. professional health care workers often know about the vaccines they need and about the vectorborne threats in the regions where they’re headed, but they may still avoid taking precautions. In addition, both lay and professional aid workers are sometimes careless or naive about other overseas risks, whether from environmental hazards, health care–associated injuries, or road accidents. One way to mitigate risks is to put in place a well-informed, carefully structured process of screening, education, supervision, and pre- and post-travel care — for which sponsoring organizations must increasingly take responsibility.

The image in clinical medicine features in chest x-ray of a 47-year-old woman with a dry cough and mild exertional dyspnea, who showed poorly defined bilateral nodular opacities in the superior lung fields. The patient had undergone renal transplantation at 23 years of age.

An axial computed tomographic scan of the chest showed centrilobular ground-glass nodules and heterogeneous attenuation, features that were suggestive of calcium deposition . Results of serum tests revealed increased serum creatinine, a normal calcium level, a normal phosphate level, increased parathyroid hormone, and a low vitamin D level. the patient received a diagnosis of metastatic pulmonary calcification due to chronic renal impairment and secondary hyperparathyroidism.

Also featured in the image in the clinical medicine is a healthy 6-year-old boy presented to the emergency department with a blistering eruption on his right middle finger. The rash had started 10 days previously as an erythematous papule and rapidly progressed into an annular plaque that soon blistered. Mycologic culture of skin scrapings showed Trichophyton rubrum, a common cause of cutaneous fungal infection.

This concludes the summary of the Dec. 23rd issue of the New England Journal of Medicine. We are interested in your feedback about our audio summaries, any comments and suggestions may be sent to audio@nejm.org. Thank you for listening.