Niraparib Maintenance Therapy in Ovarian Cancer

Posted by • December 1st, 2016


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Ovarian cancer is a leading cause of death from gynecologic cancers worldwide. A randomized, placebo-controlled, phase 3 trial conducted by Mirza et al. evaluated the efficacy and safety of niraparib versus placebo as maintenance treatment in a broad population of patients with platinum-sensitive, recurrent ovarian cancer. Among these patients, the use of niraparib, a PARP inhibitor, was associated with a significantly longer duration of progression-free survival than placebo, with moderate bone marrow toxicity. A new Original Article summarizes.

Clinical Pearl

• What is the usual pattern of response to platinum and taxane treatment in patients with advanced ovarian cancer?

Despite a high initial response rate to platinum and taxane treatment in patients with advanced cancer, the effectiveness of the treatments diminishes over time, and most patients have a relapse. Platinum retreatment is used in patients in whom there is an assumed platinum sensitivity, with diminishing effectiveness and a cumulative increase in toxicity.

Clinical Pearl

• To what class of drugs does niraparib belong?

Niraparib is a highly selective inhibitor of poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) 1/2, nuclear proteins that detect DNA damage and promote its repair. Clinical studies have evaluated PARP inhibitors in patients with recurrent ovarian cancer, including those with germline BRCA mutations, platinum-sensitive disease, or both.

Morning Report Questions

Q: Does niraparib maintenance therapy prolong progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer?

A: The trial by Mirza et al. enrolled two independent cohorts on the basis of the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort). Before the database lock, tumor testing of archived tissue samples was performed with the use of a central laboratory DNA-based test to define the population of patients in the non-gBRCA cohort in whom tumors were found to have homologous recombination deficiency (HRD). Such patients were included in the non-gBRCA HRD-positive subgroup. (Decreased rates of homologous recombination have been found to cause inefficient DNA repair.) The three predefined primary efficacy populations were the gBRCA cohort, the HRD-positive subgroup of the non-gBRCA cohort, and the overall non-gBRCA cohort. The authors found that niraparib had a positive effect among patients with platinum-sensitive recurrent ovarian cancer. The duration of progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer was significantly longer in the niraparib group than in the placebo group, regardless of the presence or absence of gBRCA mutations or HRD status.


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Q: What adverse events were associated with niraparib in the trial by Mirza et al.?

A: In the trial by Mirza et al., Grade 3 or 4 hematologic events that were observed in at least 10% of patients receiving niraparib were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%). Treatment discontinuations because of these events were infrequent. Most of the hematologic laboratory abnormalities occurred within the first three treatment cycles; after dose adjustment on the basis of an individual adverse-event profile, the incidence of grade 3 or 4 thrombocytopenia, neutropenia, or fatigue was infrequent beyond cycle 3.

Reduction in HIV Transmission with Dapivirine Vaginal Ring – Is it Enough?

Posted by • November 30th, 2016


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While you are working for one month in a health center in South Africa, a 19-year-old woman comes to the clinic and asks for your advice: She is HIV-negative, and is unsure of her partner’s HIV status. Is there anything she can do to prevent her from acquiring HIV?

Preexposure prophylaxis (PrEP) with oral tenofovir-emtricitabine is an emerging approach to prevent HIV transmission, with some data in men who have sex with men suggesting effectiveness. However, the efficacy of PrEP in women has been inconsistent, especially in young women in sub-Saharan Africa. Studies of vaginal tenofovir gel and oral tenofovir-emtricitamine in women have failed to consistently demonstrate a reduction in the risk of HIV acquisition. The limited efficacy was thought to be attributed to poor adherence and possibly a lower concentration of tenofovir in the female genital tract.

Two studies appearing in this week’s NEJM highlight a new approach to prophylaxis against HIV. Both the Ring study and the Aspire study were randomized, double-blind, placebo-controlled trials conducted in sub-Saharan Africa. These trials examined the effectiveness of a monthly self-inserted vaginal ring that contains sustained-release dapivirine, a non-nucleotide reverse transcriptase inhibitor, in healthy, nonpregnant, HIV-uninfected women aged 18-45 years who were engaged in regular sexual activity. All participants received treatment for sexually transmitted infections and a standard HIV prevention package (including regular HIV testing, counseling, and condoms).

The primary outcome in both studies was new HIV infections. In both studies, the HIV incidence rate was lower in the dapivirine group than in the placebo group. In the Ring study, incidence rates were 4.1 vs. 6.1 per 100 person-years (relative reduction, 31%) and in the Aspire study, the rates were 3.3 vs. 4.5 per 100 person-years (relative reduction, 27%). In the Aspire study, the ring did not significantly reduce HIV incidence in women ≤21 years old, but was associated with a 61% relative reduction in women >21. Adherence to treatment was good in both studies, based on pre-specified levels of plasma dapivirine concentrations and remaining dapivirine levels in returned rings.

In prior studies, poor adherence to PrEP therapies was hypothesized as the primary reason for treatment failure. The finding from these two studies that the dapivirine ring only reduced HIV acquisition by approximately 30% suggests that the ring itself had limited efficacy or that the thresholds for adherence selected by the investigators were insufficient to identify poor adherence. “Preventing HIV transmission is an important individual and public health goal and new approaches are needed. What to do with this modest effect is a challenging question for the field” says Dr. Lindsey Baden, Deputy Editor at the NEJM. Additionally, the reduced efficacy in younger women complicates the benefits.  In an accompanying editorial, Dr. Adaora A. Adimora from the Institute for Global Health and Infectious Diseases at the University of North Carolina School of Medicine concludes, “The past few years have yielded substantial progress in strategies for the prevention of HIV infection. Nevertheless, considerable work will be required to achieve safe, effective, affordable HIV prevention for all women at risk.”

Von Willebrand’s Disease

Posted by • November 24th, 2016


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Von Willebrand’s disease is an inherited bleeding disorder characterized by defective platelet adhesion and aggregation. It is the most common inherited bleeding disorder and is generally transmitted as an autosomal dominant trait. It is mainly associated with mucosal bleeding and excessive bleeding after trauma or surgery. A variety of effective treatments are available and research is summarized in a new Review Article.

Clinical Pearl

What are the different types of von Willebrand’s disease?

Von Willebrand’s disease is subdivided into types 1, 2, and 3. Type 1, which accounts for 70 to 80% of cases, is characterized by a quantitative deficiency of von Willebrand factor. Type 2, accounting for approximately 20% of cases, is caused by dysfunctional von Willebrand factor, resulting in a normal or reduced von Willebrand factor antigen concentration but a large reduction in von Willebrand factor function. Type 2 is further subdivided on the basis of specific phenotypic characteristics. Type 3 von Willebrand’s disease is rare (accounting for <5% of cases), is the most severe form, and is caused by the absence of circulating von Willebrand factor.

Clinical Pearl

What are some of the clinical features of von Willebrand’s disease?

The symptoms of von Willebrand’s disease vary among patients, depending on the level of residual von Willebrand factor activity, the disease subtype, and to some extent, age and sex. In children with von Willebrand’s disease, the most frequent presenting symptoms are bruising and epistaxis. In adults, the most common symptoms are hematomas, menorrhagia, and bleeding from minor wounds. The majority of patients (60 to 80%) have bleeding after surgery or dental extractions. A well-known, serious, and possibly life-threatening bleeding complication is gastrointestinal bleeding from angiodysplasia. It is most common in elderly patients with type 2 or 3 von Willebrand’s disease. Intraarticular (joint) bleeding is a frequent complication in patients with hemophilia but has not been reported as a major problem in patients with von Willebrand’s disease, although it may be a presenting symptom in those with type 2N (type 2 subtype Normandy) or type 3 disease. It is now known that joint bleeding occurs in a considerable number of severely affected patients, potentially leading to arthropathy and reduced joint function.

Morning Report Questions

Q: Does the progressive physiological rise in von Willebrand factor levels throughout life reduce bleeding episodes in older patients with von Willebrand’s disease?

A: As a result of the physiologic rise in von Willebrand factor levels throughout life, patients with type 1 von Willebrand’s disease may have levels within the normal range when they become older. It is still not known whether this rise results in fewer bleeding episodes. A recent study showed that among patients with type 1 disease, bleeding symptoms occurred as frequently in patients who were older than 65 years of age as in those who were 18 to 65 years of age, which suggests that the age-dependent rise in von Willebrand factor levels does not lead to a mitigation of bleeding symptoms. Even though von Willebrand factor antigen levels also rise with age in patients with type 2 disease, von Willebrand factor activity remains low because of the functional defect in the protein. In these patients, an increase in bleeding symptoms is observed with increasing age. These observations should be confirmed in larger prospective studies.

Q: What are some of the factors other than mutations in the VWF gene that may play a role in reducing von Willebrand factor levels? 

A: Even though many mutations causing type 1 von Willebrand’s disease have been identified, no mutations are found in approximately 30% of patients. Genetic modifiers outside the VWF gene and physiological factors probably play a role in reducing von Willebrand factor levels. One of the major genetic determinants of von Willebrand factor levels outside the VWF gene is the ABO blood group, with 25% lower von Willebrand factor levels in persons with type O blood than in those with other types. Genomewide association studies have identified several other genetic loci that are associated with von Willebrand factor levels in healthy persons. Studies have confirmed that these genetic loci lead to variability in von Willebrand factor levels in patients with von Willebrand’s disease, as well as in healthy persons. The newly recognized genetic loci may contribute to the variability in the von Willebrand’s disease phenotype and may explain low levels of von Willebrand factor in affected patients who do not have a mutation in the VWF gene. Apart from genetic modifiers, physiological factors such as age and the response to exercise and the acute-phase response, as well as the menstrual cycle and pregnancy in women, also play a role in the variability of von Willebrand factor levels.

A Man with Acute Liver Injury

Posted by • November 24th, 2016


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HEV infection is uncommon in the United States, although 20% of the population has antibodies to HEV. The diagnosis should be considered in patients who present with acute hepatitis after returning from a trip to an area in which HEV is endemic. In a new Case Record article, a 50-year-old man from India with a remote history of alcohol use was admitted to the hospital because of abnormal liver function test results, anemia, and acute kidney injury. A diagnosis was made.

Clinical Pearl

What are some of the features of HEV infection?

HEV is endemic throughout Central and Southeast Asia, India, the Middle East, North Africa, and Mexico. In these areas, HEV is a major cause of acute hepatitis and acute liver failure, with high attack rates among adults between 15 and 40 years of age. HEV is transmitted enterically and is responsible for waterborne outbreaks of hepatitis; person-to-person transmission is uncommon. The mean incubation period is 40 days. A high mortality rate (15 to 25%) occurs among pregnant women. The risk of hepatic decompensation is increased in patients with underlying chronic liver disease.

Clinical Pearl

What is the usual course of hepatitis E virus infection?

Illness is generally self-limited, but cases of chronic hepatitis attributed to HEV that have progressed rapidly to cirrhosis have been reported in transplant recipients and, rarely, in persons with human immunodeficiency virus infection or preexisting liver disease or in those undergoing chemotherapy for cancer.

Morning Report Questions

Q: Are there reliable serologic tests for diagnosing acute hepatitis E available in the United States? 

A: The diagnosis of acute hepatitis E is made most readily by testing for anti-HEV IgM antibodies in serum, although available tests may not be reliable and are not licensed for use in the United States. The diagnosis can also be made by detecting HEV in serum or stool with the use of a polymerase-chain-reaction (PCR) assay. A liver biopsy is generally unnecessary. However, serologic testing for HEV should be interpreted with caution, because the test has several limitations, including variability in the sensitivity and specificity of tests available in the United States.

Q: Is there an established role for antiviral therapy in cases of acute hepatitis E infection? 

A: Antiviral treatments for acute HEV infection have not been well studied; most of the literature on treatment involves reports of immunocompromised patients with chronic HEV infection. When decreasing the immunosuppression is not feasible or does not lead to viral clearance, antiviral therapy with pegylated interferon alone or in combination with ribavirin has been shown to be effective. Whether antiviral treatment with ribavirin improves outcomes in patients with severe acute HEV infection is unknown, but several case reports suggest a benefit. However, ribavirin is also associated with a substantial risk of hemolytic anemia. There is evidence that acute HEV infection can resolve without antiviral therapy.

Thresholds for Abdominal Aortic Aneurysm Repair in England and the United States

Posted by • November 23rd, 2016


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Imagine you are assessing a relatively healthy 85-year-old man who was brought to the hospital after a fall at home. Due to concern for spinal fractures, he underwent CT scans of his head, C-spine, chest, abdomen, and pelvis. Although no traumatic injuries were found, an incidental finding of a 5.5 cm infrarenal abdominal aortic aneurysm (AAA) was noted on the CT scan of the abdomen. The patient is asymptomatic from this aneurysm with no complaints of abdominal pain, back pain, or syncopal episodes. Should he undergo aneurysm repair? Can you watch and wait? Is he at risk for aneurysm rupture if you don’t intervene?

International guidelines recommend aneurysm repair once aneurysm diameter exceeds 5.5 cm for men and 5.0 cm for women. However, these guidelines are not applied universally and there is still uncertainty about the ideal diameter for intervention. In this week’s NEJM, Karthikesalingam et al. compared thresholds for AAA repair in the U.S. and England and differences in rates of aneurysm repair, in-hospital mortality, aneurysm rupture, long-term survival, aneurysm-related mortality, preoperative aneurysm diameter at time of repair, and prevalence of risk factors.  The authors used several unlinked databases and stratified the comparisons by age and gender. Survival comparisons also were adjusted for year of surgery and whether the repair was open or endovascular.

Rates of intact aneurysm repair increased in both countries from 2005–2012, but rates were significantly lower in England (odds ratio, 0.49; P<0.0001). The percentage of repairs that were endovascular was also lower in England (45% vs. 67%, P<0.001).  After controlling for multiple factors, in-hospital mortality and 3-year survival after elective repair were similar in the two countries.

Although rates of hospitalization for aneurysm rupture decreased in both countries from 2005–2012, hospitalization was significantly more common in England (OR, 2.23; P<0.001). Aneurysm –related mortality also declined in both countries, but again was significantly higher in England (OR, 3.60; P<0.001). The mean aneurysm diameter (weighted for age and gender) at intact AAA repair was significantly larger in England than in the U.S. (6.37 vs. 5.83 cm; P<0.001).

The study authors conclude that the rate of intact AAA repair in England is about half as high as in the U.S., likely because surgeons in England repair aneurysms when they are larger than surgeons in the U.S. The higher rate of intact aneurysm repair at a lower diameter in the U.S. did not appear to increase perioperative risk or mortality. In fact, the authors suggest that the higher rate of ruptured aneurysm hospitalization and mortality in England may be due to the higher-diameter aneurysm repair thresholds.

The major weakness of this study is that the authors cannot establish a causal relationship between the increased rates of aneurysm-rupture outcomes in England and the threshold at which they repair aneurysms. In addition, this study is limited by the retrospective design and the use of several unlinked databases during different time periods. Although this study is unlikely to change practice, it does provide more support for the existing international guidelines and may lead some countries to reconsider AAA repair thresholds.

Acute Pancreatitis

Posted by • November 17th, 2016


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Approximately 80% of patients admitted with acute pancreatitis have mild, self-limited disease and are discharged within several days. Mortality associated with acute pancreatitis has decreased over time, and the overall mortality is now approximately 2%. A new Review Article summarizes recent changes in the management of acute pancreatitis, encompassing fluid resuscitation, antibiotic use, nutritional support, and treatment of necrosis, and also addresses common misunderstandings and areas of controversy.

Clinical Pearl

What are some of the factors that might contribute to unexplained pancreatitis?

The cause of acute pancreatitis often cannot be established, and the proportion of persons who are considered to have idiopathic acute pancreatitis increases with age. A number of potential factors might contribute to unexplained pancreatitis, including unidentified genetic polymorphisms, exposure to smoking and other environmental toxins, and effects of coexisting diseases that are commonly associated with acute pancreatitis (e.g., obesity and diabetes).

Clinical Pearl

What is the role of prophylactic antibiotics in acute pancreatitis?

Although the development of infected pancreatic necrosis confers a significant risk of death, well-designed trials and meta-analyses have shown no benefit of prophylactic antibiotics. Prophylaxis with antibiotic therapy is not recommended for any type of acute pancreatitis unless infection is suspected or has been confirmed.


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Morning Report Questions

Q: Should patients with acute pancreatitis receive enteral or parenteral nutrition? 

A: Total parenteral nutrition is now known to be more expensive, riskier, and no more effective than enteral nutrition in patients with acute pancreatitis. In patients with mild acute pancreatitis who do not have organ failure or necrosis, there is no need for complete resolution of pain or normalization of pancreatic enzyme levels before oral feeding is started. A low-fat soft or solid diet is safe and associated with shorter hospital stays than is a clear-liquid diet with slow advancement to solid foods. Most patients with mild acute pancreatitis can be started on a low-fat diet soon after admission, in the absence of severe pain, nausea, vomiting, and ileus (all of which are unusual in mild cases of acute pancreatitis). A need for artificial enteral feeding may be predicted by day 5, on the basis of symptoms that continue to be severe or an inability to tolerate attempts at oral feeding. Although nasojejunal tube feeding is best for minimizing pancreatic secretion, randomized trials and a meta-analysis have shown that nasogastric or nasoduodenal feeding is clinically equivalent. Total parenteral nutrition should be reserved for the rare cases in which enteral nutrition is not tolerated or nutritional goals are not met. Unfortunately, total parenteral nutrition continues to be used frequently in patients with acute pancreatitis.

Q: What is the risk of recurrent gallstone pancreatitis if cholecystectomy is delayed?

A: Cholecystectomy prevents recurrent gallstone pancreatitis. A delay of cholecystectomy for more than a few weeks places the patient at a high (up to 30%) risk for relapse. Cholecystectomy performed during the initial hospitalization for mild pancreatitis due to gallstones reduces the rate of subsequent gallstone-related complications by almost 75%, as compared with cholecystectomy performed 25 to 30 days after discharge. For patients with severe or necrotizing pancreatitis, cholecystectomy may be delayed in order to address other clinically significant conditions or provide time for the pancreatic inflammation to diminish, allowing for better operative exposure.

Ustekinumab for Crohn’s Disease

Posted by • November 17th, 2016


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In a previous phase 2b trial, intravenous ustekinumab induction therapy in patients with Crohn’s disease that was refractory to treatment with tumor necrosis factor (TNF) antagonists showed a significant benefit in terms of clinical response but not remission, and subcutaneously administered maintenance doses of ustekinumab were efficacious during a period of 22 weeks. Feagan et al. randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to TNF antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The research is summarized in a new Original Article.

Clinical Pearl

What are some of the limitations of current therapies for Crohn’s disease?

Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract that is treated with glucocorticoids, immunosuppressants, TNF antagonists, or integrin inhibitors. The drawbacks of these agents include an increased risk of infection and cancer and limited efficacy.

Clinical Pearl

What is ustekinumab?

Ustekinumab is a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23 that has been approved for use in the treatment of psoriasis and psoriatic arthritis. In previous trials involving patients with psoriasis in which ustekinumab was administered subcutaneously for up to 5 years, the drug was not associated with an increased risk of serious adverse events.

Morning Report Questions

Q: Is ustekinumab effective as induction and maintenance therapy in Crohn’s disease?

A: At week 0 in the trial by Feagan et al., patients in both induction trials were randomly assigned, in a 1:1:1 ratio, to receive a single intravenous infusion of 130 mg of ustekinumab, a weight-range–based dose that approximated 6 mg of ustekinumab per kilogram of body weight, or placebo. (The administration of 6 mg of ustekinumab per kilogram meant that patients weighing ≤55 kg received 260 mg, those weighing >55 kg and ≤85 kg received 390 mg, and those weighing >85 kg received 520 mg.) In the maintenance trial, patients who had a response to ustekinumab induction therapy at week 8 were randomly assigned, in a 1:1:1 ratio, to receive subcutaneous injections of 90 mg of ustekinumab every 8 weeks, 90 mg of ustekinumab every 12 weeks, or placebo through week 40. In both induction trials, the primary end point was clinical response at week 6, which was defined as a decrease from baseline in the Crohn’s Disease Activity Index (CDAI) score of at least 100 points or a total CDAI score less than 150. In the maintenance trial, the primary end point was clinical remission at week 44 (CDAI score <150). Both ustekinumab induction regimens showed consistent benefit over placebo, irrespective of previous treatment or response to a TNF antagonist. Ustekinumab was significantly better than placebo with respect to the primary and all major secondary end points for induction at both doses, with the highest rates of response and remission observed with the dose of 6 mg per kilogram. At week 44 of the maintenance trial, among those who had a response to ustekinumab during induction, both subcutaneous ustekinumab doses showed significantly higher efficacy than placebo.

Q: Did the trial by Feagan et al. raise new safety concerns regarding the use of ustekinumab in patients with Crohn’s disease?

A: In the trial by Feagan et al., there were no deaths, and rates of overall adverse events, serious adverse events, and adverse events within 1 hour after infusion occurred at similar rates across groups. The rates of adverse events were similar for subcutaneous maintenance therapy with ustekinumab and placebo, and there was no apparent relationship between dose and safety. The adverse events observed in these trials are consistent with 5 years of cumulative data acquired for patients with psoriasis (who received subcutaneous doses ≤90 mg) and 2 years of safety data for patients with psoriatic arthritis.

Effect of Short-Term vs. Long-Term Blood Storage on Mortality after Transfusion

Posted by • November 16th, 2016


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The FDA currently allows donated units of blood to be stored for 42 days. However, questions remain about whether older blood (within the 42-day limit) is harmful. Laboratory studies have shown that older blood has decreased levels of 2,3-diphosphoglycerate, decreased nitric oxide metabolism, impaired membrane deformability, and increased adherence to the endothelium, all of which theoretically decrease oxygen delivery to tissues. A retrospective study in cardiac surgery patients reported an association between older blood and increased mortality. However, several randomized trials in various patient populations, including pre-term infants and critically ill adults, have not.

In the Informing Fresh versus Old Red Cell Management (INFORM) Trial, published in this week’s NEJM, investigators performed the largest trial to date to assess the effects of the age of transfused blood on patient outcomes. In this study, 20,858 patients requiring blood transfusion in six hospitals across four countries from 2012 to 2015 were randomized to receive either the freshest available blood in the bank (median storage, 11 days) or the oldest blood in the bank (median storage, 23 days). Only patients with the most common blood types, types A and O, were included in the primary analysis because the increased availability of these donated blood units was expected to allow at least a 10-day mean difference between the oldest and freshest blood in the blood banks.

The primary outcome, in-hospital mortality, did not differ between patients who received the freshest blood and those who received the oldest blood (9.1% vs 8.7%, P=0.34). Furthermore, there were no significant mortality differences in three pre-specified high-risk subgroups including patients in the ICU, patients with cancer, and those undergoing cardiothoracic surgery. When these analyses were repeated by blood type, the results were similar.

In an accompanying editorial, Drs. Aaron Tobian and Paul Ness from the Division of Transfusion Medicine at Johns Hopkins University praise the study design for its large size, evaluating many more patients than all previous trials combined and thereby allowing a robust mortality analysis. They also highlight the pragmatic design of the INFORM trial, noting its potential “as a model for other trials” by using electronic data, waived consent, and an easily-assessed outcome (mortality), all of which markedly reduced cost. However, the editorialists caution, “Even though the results of the INFORM trial should end the debate regarding whether short-term or long-term storage of blood is advantageous, the question is still open as to whether the transfusion of red cells during the last week of storage (35 to 42 days) poses more risk than the transfusion of blood stored for shorter intervals.”

The INFORM study answers important questions about outcomes for patients receiving blood transfusions of varying degrees of freshness using a pragmatic trial design. The large number and diversity of patients allows for greater generalizability, and further affirms previous studies that demonstrate no difference in mortality outcomes. John Jarcho, deputy editor at NEJM, noted, “This large trial should really settle the question of whether current storage policies are adequate to maintain the quality of the blood supply.”

wei-koWei Ko is a 4th year medical student at the University of Massachusetts Medical School

Take the Case Challenge: A Man with Acute Liver Injury

Posted by • November 14th, 2016


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A 50-year-old man was admitted to the hospital because of increased levels of aminotransferases, hyperbilirubinemia, anemia, and acute kidney injury. What is the most likely diagnosis?

Read the case description then vote and comment on what you think the diagnosis is. Review the answers in the full text of the case to be published in the November 24 issue and continue following the conversation on Facebook and Twitter with #NEJMCases.

Heart Failure with Preserved Ejection Fraction

Posted by • November 10th, 2016


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Epidemiologic studies indicate that up to 50% of patients with heart failure have a preserved ejection fraction, and this proportion has increased over time. In observational studies, rates of hospitalization and death among patients who have heart failure with a preserved ejection fraction approach those among patients who have heart failure with a reduced ejection fraction, but in clinical-trial populations, outcomes are better in patients who have heart failure with a preserved ejection fraction. Management of heart failure with preserved ejection fraction includes diuretics, treatment of coexisting conditions, aerobic exercise, self-care, and disease management programs, but medications that are effective for reduced ejection fraction have not been beneficial. A new Clinical Practice article explains further.

Clinical Pearl

• How is heart failure with a preserved ejection fraction defined?

In observational studies and clinical trials, the value used to define a “preserved” ejection fraction has ranged from 40 to 55%, but current guidelines recommend a partition value of 50%. An ejection fraction of 40 to 49% is a gray area.

Clinical Pearl

Is the pathophysiology of heart failure with a preserved ejection fraction well understood?

The fundamental pathophysiology perturbation leading to heart failure with a preserved ejection fraction remains incompletely defined, but traditionally it has been attributed to hypertensive left ventricular remodeling. Systemic microvascular endothelial inflammation related to coexisting conditions has been proposed as an additional mechanism leading to myocardial inflammation and fibrosis, increases in oxidative stress, and alterations in cardiomyocyte signaling pathways. These alterations promote cardiomyocyte remodeling and dysfunction as well as microvascular dysfunction and rarefaction in cardiac and skeletal muscle.

Morning Report Questions

Q: Are circulating levels of natriuretic peptides elevated in patients with heart failure and preserved ejection fraction?

A: Ventricular wall stress and thus circulating levels of natriuretic peptides are lower in patients who have heart failure with a preserved ejection fraction than in patients who have heart failure with a reduced ejection fraction. Levels of natriuretic peptides may be normal in up to 30% of patients who have heart failure with a preserved ejection fraction, particularly in those who are obese or have purely exertional symptoms. The higher the natriuretic peptide level, the more likely it is that the patient has heart failure. However, some elderly patients or patients who have atrial fibrillation without heart failure may have natriuretic peptide levels that are similar to those of patients with heart failure.

Q: What is the role of angiotensin antagonists, spironolactone, and beta-blockers in the management of heart failure with a preserved ejection fraction?

A: Since no therapy has been shown to improve outcomes in patients who have heart failure with a preserved ejection fraction, current therapy includes the relief of volume overload (when present), treatment of coexisting conditions, additional strategies that may increase exercise tolerance or reduce symptoms, and strategies to manage chronic disease and prevent hospitalizations. Individually or in a meta-analysis, three randomized trials of angiotensin antagonists (angiotensin-converting–enzyme [ACE] inhibitors or angiotensin-receptor antagonists) involving patients who had heart failure with a preserved ejection fraction did not show significant effects of these agents on composite end points of all-cause or cardiovascular mortality and hospitalizations for heart failure. The mineralocorticoid-receptor antagonist spironolactone did not reduce rates of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure in these patients. Spironolactone reduced the rate of hospitalization for heart failure but not the rate of death from any cause or hospitalization for any cause, and it increased the rate of renal dysfunction and hyperkalemia. Analyses that were limited to patients who were enrolled in centers in the Americas (which had higher event rates) showed beneficial effects of spironolactone on the composite primary end point, but these post hoc analyses must be interpreted with caution. The effect of beta-blockers in patients with heart failure and a preserved ejection fraction has not been evaluated in an adequately powered study, and the limited available data are conflicting. Thus, the use of angiotensin antagonists and beta-blockers in the treatment of patients who have heart failure with a preserved ejection fraction should be limited to patients who have alternative indications for their use.


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