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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Semaglutide in Patients with Type 2 Diabetes

Posted by • November 10th, 2016

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Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The preapproval Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) conducted by Marso et al. was designed to assess the noninferiority of semaglutide as compared with placebo in terms of cardiovascular safety in patients with type 2 diabetes. Patients with type 2 diabetes at high cardiovascular risk received either once-weekly semaglutide, a glucagon-like peptide 1 analogue, or placebo. The rate of a first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke was significantly lower with semaglutide. Research is summarized in a new Original Article.

Clinical Pearl

To what class of drug does semaglutide belong?

Semaglutide, a glucagon-like peptide 1 (GLP-1) analogue with an extended half-life of approximately 1 week (which permits once-weekly subcutaneous administration), is currently in development but not yet approved for the treatment of type 2 diabetes. In the SUSTAIN-6 trial, patients were randomized in a 1:1:1:1 ratio to receive either 0.5 mg or 1.0 mg of once-weekly subcutaneous semaglutide or volume-matched placebo, which maintained blinding within dose.

Clinical Pearl

Is semaglutide noninferior to placebo with respect to cardiovascular safety in patients with type 2 diabetes?

The study by Marso et al. confirmed the authors’ primary hypothesis that semaglutide would be noninferior to placebo. Semaglutide-treated patients had a significant 26% lower risk of the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke than did those receiving placebo. This lower risk was principally driven by a significant (39%) decrease in the rate of nonfatal stroke and a nonsignificant (26%) decrease in nonfatal myocardial infarction, with no significant difference in the rate of cardiovascular death. Similar risk reductions were observed with both doses of semaglutide. The number of patients who would need to be treated to prevent one event of the primary outcome over a period of 24 months was 45 on the basis of Kaplan–Meier estimates. The risk reduction for the primary outcome was seen despite an increase in pulse rate, a class effect for GLP-1–receptor agonists.

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Morning Report Questions

Q: Does the use of semaglutide in patients with type 2 diabetes improve microvascular outcomes?

A: In the study by Marso et al., semaglutide-treated patients had a lower risk of new or worsening nephropathy, according to differences in macroalbuminuria, but a higher risk of diabetic retinopathy complications than did those receiving placebo. Although the overall number of retinopathy events was low, there was an unexpected higher rate of retinopathy complications (vitreous hemorrhage, blindness, or the need for treatment with an intravitreal agent or photocoagulation) in the semaglutide group. An association between rapid glucose lowering and worsening of retinopathy has been reported in patients with type 1 diabetes. The applicability of such an association to the finding in SUSTAIN-6 is unclear, and a direct effect of semaglutide cannot be ruled out.

Q: How does semaglutide compare to other GLP-1–receptor agonists?

A: With the exception of complications of retinopathy, semaglutide had a safety profile in SUSTAIN-6 similar to that of other GLP-1–receptor agonists. The rate of malignant neoplasms was similar in the pooled semaglutide group and the pooled placebo group, although the highest rate was observed with the semaglutide dose of 1.0 mg. The rate of pancreatic cancer — an event of interest for this drug class — was lower with semaglutide, and no medullary thyroid carcinomas were reported in this trial. Pancreatitis occurred in low yet similar numbers of patients in the two pooled groups.

Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck

Posted by • November 9th, 2016

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A 62-year-old man with a history of smoking and excess alcohol use presented with a two-month history of hoarseness and dysphagia and was diagnosed with laryngeal squamous cell carcinoma. Five months after completing concurrent cisplatin and radiation therapy, he returns to his oncologist with lung metastases. He asks about additional therapeutic options for his cancer diagnosis. How would you advise him?

This patient is one of 52,000 people in the United States diagnosed every year with squamous-cell carcinoma of the head and neck (SCCHN). SCCHN is a worldwide condition that arises from squamous cells lining mucosal surfaces of the head and neck. It is associated with alcohol and tobacco use, poor oral hygiene, consuming certain preserved foods, chewing betel nuts, and infection with human papillomavirus or Epstein-Barr virus. Recurrent SCCHN is thought to be driven by immune evasion via tumor expression of ligands (PD-L1) for the immune-checkpoint receptor programmed death-1 (PD-1). Therefore, nivolumab — an anti–PD-1 monoclonal antibody — represents a potential therapeutic candidate. Nivolumab has been approved for treatment of metastatic melanoma, non-small cell lung cancer, and renal cell carcinoma.

In this week’s issue of NEJM, Ferris and colleagues compared the efficacy of nivolumab to single-agent systemic chemotherapy in a phase 3 randomized, controlled, open-label study in 361 patients with recurrent SCCHN whose disease had progressed within six months after platinum-based chemotherapy. Patients in the nivolumab group received intravenous nivolumab (3 mg/kg) every two weeks. Patients in the single-agent chemotherapy group received a weekly dose of intravenous methotrexate (40–60 mg/m2), docetaxel (30–40 mg/m2), or cetuximab (250 mg/m2) after a loading dose of 400 mg/m2. The primary endpoint was overall survival, defined as the time from randomization to date of death from any cause. Secondary endpoints were progression-free survival, objective tumor response based on imaging, safety, and quality of life.

Among the 240 patients who received nivolumab and the 121 patients who received single-agent chemotherapy, median overall survival was significantly longer in the nivolumab group (7.5 vs. 5.1 months; hazard ratio, 0.70; 97.73% CI: 0.51 to 0.96; P=0.010). Progression-free survival did not differ significantly between the two groups. The authors performed an exploratory biomarker analysis to compare the treatment effect in patients based on their tumor PD-L1 expression status and p16 status. Median overall survival was longer with nivolumab, regardless of tumor PD-L1 expression or p16 status.

Nivolumab was associated with fewer severe adverse events than single-agent chemotherapy (13.1% vs. 35.1%). The most frequently reported adverse events with nivolumab were fatigue, rash, pruritus, nausea, and decreased appetite. Nivolumab was associated with more skin-related side effects and fewer gastrointestinal events than single-agent chemotherapy. Serious adverse events in the nivolumab group included one case of pneumonitis and one report of hypercalcemia. Patients in the nivolumab group reported better quality of life (including physical functioning, pain, sensory problems, and social contact problems) than patients in the single-agent chemotherapy group.

In this study, nivolumab led to improved overall survival, fewer severe adverse events, and better quality of life in patients with recurrent SCCHN refractory to platinum-based chemotherapy. Importantly, nivolumab not only extended overall survival but also contributed to better functioning for patients with this aggressive cancer that often affects vital areas of speech and swallowing.

jenniferyehJennifer Yeh is an eighth-year MD/PhD student at Harvard Medical School. She is originally from Los Angeles, CA, and graduated from the Massachusetts Institute of Technology in 2009. She completed her PhD in Biological & Biomedical Sciences in 2015 on molecular modulators of the oncogenic transcription factor STAT3 in the lab of Dr. David Frank.

Ribociclib for HR-Positive Breast Cancer

Posted by • November 3rd, 2016

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Hortobagyi et al. conducted the Mammary Oncology Assessment of LEE011’s (Ribociclib’s) Efficacy and Safety (MONALEESA-2) trial, which evaluated the efficacy and safety of the combination of ribociclib and letrozole as initial therapy in postmenopausal women with hormone-receptor (HR)–positive, human epidermal growth factor 2 (HER2)–negative advanced breast cancer. In patients with advanced HR-positive, HER2-negative breast cancer, the addition of the cyclin-dependent kinase inhibitor ribociclib to letrozole was associated with a significantly higher rate of progression-free survival than placebo. A new Original Article explains.

Clinical Pearl

What percentage of breast cancers are HR-positive?

Up to 75% of breast cancers express the estrogen receptor or progesterone receptor (HR-positive). Endocrine therapy is the standard of care for postmenopausal women with advanced breast cancer that is HR-positive and HER2-negative, with aromatase inhibitors being the preferred first-line treatment option. However, in the majority of patients, resistance to currently available options eventually develops, which requires the administration of sequential therapy with alternative endocrine regimens.

Clinical Pearl

What is ribociclib?

Ribociclib (LEE011) is an orally bioavailable, selective, small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) that blocks the phosphorylation of retinoblastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. CDK4/6 in conjunction with their protein regulator, cyclin D1 (encoded by CCND1), a direct transcriptional target of estrogen-receptor signaling, are mediators of cell-cycle progression. CDK4/6 overexpression and CCND1 amplification are frequently encountered in HR-positive breast cancers and are key mediators of endocrine resistance. The inhibition of a pathway consisting of cyclin D, CDK4/6, inhibitor of CDK4 (INK4), and retinoblastoma protein is an effective therapeutic strategy for HR-positive advanced breast cancer, both as a first-line option and in patients in whom disease has progressed while they were receiving endocrine therapy.

Morning Report Questions

Q: Does the combination of ribociclib and letrozole increase progression-free survival as compared to letrozole plus placebo when used as first-line therapy for HR-positive advanced breast cancer? 

A: At the prospectively planned interim analysis, the authors of the MONALEESA-2 trial found that postmenopausal women with HR-positive, HER2-negative advanced breast cancer who were receiving first-line treatment with ribociclib plus letrozole had a significantly longer duration of progression-free survival than did those receiving placebo plus letrozole, with a 44% lower relative risk of progression. The duration of progression-free survival was longer in all preplanned patient subgroups receiving ribociclib, including those with newly diagnosed or pretreated metastatic disease and those with or without liver or lung metastases. Further analyses of these subgroups are ongoing. Ribociclib plus letrozole was also associated with significantly higher rates of overall response and clinical benefit than was placebo plus letrozole, a finding that was consistent with observations from an earlier phase 1 trial.

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Q: What are some of the adverse events associated CDK4/6 inhibitors?

A: In the MONALEESA-2 trial, the most common grade 3 or 4 adverse events (≥5% of the patients in either group) were neutropenia (59.3% in the ribociclib group and 0.9% in the placebo group), leukopenia (21.0% and 0.6%, respectively), hypertension (9.9% and 10.9%), increased alanine aminotransferase level (9.3% and 1.2%), lymphopenia (6.9% and 0.9%), and increased aspartate aminotransferase level (5.7% and 1.2%). Hematologic adverse events in the ribociclib group reflected on-target CDK4/6 inhibition, which resulted in reversible bone marrow stem-cell quiescence. Elevations in alanine and aspartate aminotransferase levels have also been observed with other CDK4/6 inhibitors in combination with aromatase inhibitors.

Just a Cut

Posted by • November 3rd, 2016

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Vibrio is a gram-negative rod that is typically found in warm saltwater, although it has been isolated in waters as cold as 17°C. Vibrio infections can rapidly progress to septicemia and death and often require major amputation in patients who survive. A 51-year-old surgeon lacerated his left ring finger near the volar distal interphalangeal joint with a fillet knife while cleaning fish after a late summer day of fishing in coastal New England seawaters. Twelve hours later, he awoke with throbbing pain in his fingertip. A new Clinical Problem-Solving article summarizes the case.

Clinical Pearl

What are the clinical signs of infectious flexor tenosynovitis?

The four so-called Kanavel signs for infectious flexor tenosynovitis include flexor-sheath tenderness, circumferential swelling (a “sausage digit”), pain with passive stretch, and flexed posture. All these signs are not necessarily present in patients with tenosynovitis, particularly in those who present early.

Clinical Pearl

What are some of the pathogens to consider when soft-tissue infection develops in a wound that has been exposed to seawater?

The potential inoculation of seawater necessitates special consideration. Streptococcus iniae, which has been linked to exposure to fish, is a potential pathogen. Waterborne pathogens including aeromonas species and Mycobacterium marinum are associated with skin and soft-tissue infections. Aeromonas can cause severe infection with systemic symptoms; aeromonas is most commonly isolated from fresh or brackish water. M. marinum infection typically manifests as a more subacute or chronic infection rather than as a fulminant infection with systemic symptoms. In contrast, vibrio species, particularly Vibrio vulnificus, can cause rapidly progressive infections.

Morning Report Questions

Q: Which vibrio species are associated with soft-tissue infection, and what patient factors increase the risk of death from such infections?

A: V. vulnificus and V. parahaemolyticus species are most frequently associated with soft-tissue infection. V. vulnificus species account for most severe vibrio infections and the majority of deaths that are attributed to these infections in the United States. V. vulnificus infections can rapidly become fatal, progressing from an initial presentation of cellulitis, tenosynovitis, or necrotizing fasciitis to septicemia and death within 48 to 72 hours. Signs and symptoms of vibrio sepsis and necrotizing fasciitis include fevers and chills, localized severe swelling, rapidly painful cellulitis, purpura, and hemorrhagic bullae. According to CDC epidemiologic surveillance data, the mortality rate is 50% among patients presenting with V. vulnificus septicemia and 15% among those with wound infection without septicemia. Underlying immunosuppression, chronic illness, and liver disease are frequently cited risk factors for poor outcomes with vibrio infection, with liver disease in particular conferring a significant increase in the risk of death from wound infection.

Q: What antibiotics are used to treat V. vulnificus infection?

A: There are no definitive data from humans to guide appropriate antimicrobial therapy for V. vulnificus infection, but in vitro data and data from studies in mice have both shown efficacy with fluoroquinolones and synergistic effects of tetracycline derivatives with third-generation cephalosporins. Ampicillin–sulbactam does not provide adequate coverage for V. vulnificus.

Fulminant Myocarditis with Combination Immune Checkpoint Blockade

Posted by • November 2nd, 2016

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Oncologists and patients with cancer eagerly await new therapies that efficiently target cancer and avoid damage to normal tissues. In 2015, a randomised controlled trial investigated the role of two immune checkpoint inhibitors: ipilimumab — an anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody — and nivolumab — an anti-programmed death-1 (PD-1) antibody. Patients with untreated metastatic melanoma were randomized to receive monotherapy with one of the two agents or a combination of both agents. Results from this seminal study showed that nivolumab alone, or in combination with ipilimumab, led to significantly longer progression-free survival, compared to ipilimumab alone. In subgroup analysis, combination therapy was more effective than monotherapy with either agent in PD-L1-negative tumors. Another important study published in the same year confirmed the benefit of combination therapy compared to ipilimumab alone in metastatic melanoma.

In both studies, combination therapy was associated with higher rates of adverse events than monotherapy. Most adverse events were related to inflammation or “-itis” (including dermatitis, hypophysitis, colitis, hepatitis, and pneumonitis) and were managed with high-dose glucocorticoids that were slowly tapered until resolution of symptoms or biochemical abnormalities.

In this week’s NEJM, Johnson and colleagues report two cases of lethal myocarditis accompanied by myositis in patients treated with nivolumab and ipilimumab. Both patients had metastatic melanoma, presented with severe cardiac symptoms within two weeks of the first dose, and had a history of hypertension but no other cardiac risk factors. In both cases, the electrocardiograms were abnormal with progressive and refractory cardiac rhythm instability associated with a rise in cardiac enzymes and creatinine phosphokinase levels. Although one patient was promptly started on high-dose glucocorticoids, she died from multisystem organ failure. The other patient was treated with a temporary pacemaker, glucocorticoids, and infliximab, but he suffered fatal cardiac arrest.

Postmortem analysis of tissue samples confirmed myocarditis and myositis and excluded viral causes. Investigators reviewed the nature of the immune infiltrates in postmortem myocardial and skeletal samples in both patients. T-cell receptor next generation sequencing was used to assess the distribution, clonality, and diversity of the infiltrating lymphocytes in the tumor and damaged tissues. Selective clonal T-cell populations within the myocardium were identical to those detected in the tumor and skeletal muscle, suggesting that the same T-cell clones recognized antigens that were present on the myocardium, skeletal muscle, and tumor. The manufacturer of these agents (Bristol-Myers-Squibb) reviewed the prevalence of myocarditis in their database of more than 20,000 patients and found that combination therapy resulted in myocarditis in 0.27% of cases and myositis in 0.24% of cases.

As we enter the age of immunotherapy, it is important to adopt a multidisciplinary approach to manage toxicities. Cancer therapies such as anthracyclines, radiotherapy, and tyrosine kinase inhibitors have been associated with cardiac toxicity. Immune mediated myocarditis is a concerning adverse event that can present early, with nonspecific symptoms, and can be fatal. Although immune checkpoint inhibitors improve outcomes for patients with metastatic melanoma, clinicians need to be vigilant about recognizing nonspecific symptoms in patients treated with combination immunotherapy.

New Interactive Medical Case: “Dissecting a Case of Abdominal Pain”

Posted by • October 31st, 2016

interactive-medical-case-blog-post-picA 43-year-old man with no notable medical history presented to the emergency department within 1 hour after the abrupt onset of abdominal pain. The patient stated that he had been dressing for work when severe, “crampy” abdominal pain occurred in the left upper quadrant. On a scale of 0 to 10, with 0 indicating no pain and 10 the worst imaginable pain, the patient rated the pain at 10. After the onset of pain, the patient had nausea, several episodes of nonbilious, nonbloody emesis, and flatus.

Test your diagnostic and therapeutic skills with this free Interactive Medical Case! Video, animation, and interactive content allow you to receive feedback on your choices made based on a series of questions and exercises, review the condition and optimal treatment steps involved in a complex evolving patient history, and earn CME credit or MOC points.

You can also browse through a list of 42 previous Interactive Medical Cases and polish your skills in a wide range of medical scenarios.

Long-Term Oxygen for COPD

Posted by • October 27th, 2016

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Two trials that were conducted in the 1970s showed that long-term treatment with supplemental oxygen reduced mortality among patients with chronic obstructive pulmonary disease (COPD) and severe resting hypoxemia. In the 1990s, two trials evaluated long-term treatment with supplemental oxygen in patients with COPD who had mild-to-moderate daytime hypoxemia; neither trial showed a mortality benefit, but both were underpowered to assess mortality. The effects of oxygen treatment on hospitalization, exercise performance, and quality of life are unclear. The Long-Term Oxygen Treatment Trial assessed the potential benefits of supplemental oxygen among patients with COPD and moderate resting desaturation or exercise-induced desaturation. In this trial, long-term supplemental oxygen treatment did not result in longer survival than no use of supplemental oxygen among patients with stable COPD and moderate resting desaturation (Spo2, 89 to 93%) or moderate exercise-induced desaturation. A new Original Article explains.

Clinical Pearl

What are the estimated oxygen-related costs for patients with COPD in the United States?

Medicare reimbursements for oxygen-related costs for patients with COPD exceeded $2 billion in 2011. If long-term treatment with supplemental oxygen reduces the incidence of COPD-related hospitalizations, increased use could be cost-effective. Reliable estimates of the number of prescriptions for supplemental oxygen that are written for the indication of exercise-induced desaturation are unavailable. Data suggest that many patients with advanced emphysema who are prescribed oxygen may not have severe resting hypoxemia.

Clinical Pearl

What Spo2 values (oxyhemoglobin saturation), as measured by pulse oximetry, are consistent with moderate resting desaturation and moderate exercise-induced desaturation?

In the Long-Term Oxygen Treatment Trial, a total of 14 regional clinical centers and their associated sites (a total of 47 centers) screened patients who had stable COPD and moderate resting desaturation (Spo2, 89 to 93%) or moderate exercise-induced desaturation (during the 6-minute walk test, Spo2 ≥80% for ≥5 minutes and <90% for ≥10 seconds).

Morning Report Questions

Q: Are there benefits to long-term supplemental oxygen for patients with COPD who have moderate resting or exercise-induced hypoxemia?

A: The authors of the Long-Term Oxygen Treatment Trial found that the prescription of supplemental oxygen for patients with stable COPD and resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization, time to death, time to first hospitalization, time to first COPD exacerbation, time to first hospitalization for a COPD exacerbation, the rate of all hospitalizations, the rate of all COPD exacerbations, or changes in measures of quality of life, depression, anxiety, or functional status. The authors found no effect on the primary outcome in subgroups of patients defined according to desaturation type, prescription type, or adherence to the regimen. The consistency of the null findings strengthens the overall conclusion that long-term supplemental oxygen in patients with stable COPD and resting or exercise-induced moderate desaturation has no benefit with regard to the multiple outcomes measured.

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Q: How do the results of the Long-Term Oxygen Treatment Trial compare with some of the earlier studies of supplemental oxygen in patients with COPD?

A: The data from the Long-Term Oxygen Treatment Trial support the conclusions of earlier studies that among patients with COPD who have a resting Spo2 of more than 88%, long-term treatment with supplemental oxygen does not result in longer survival than no long-term supplemental oxygen therapy, regardless of whether the patients have exercise-induced desaturation. The findings contrast with the prolonged survival that was observed among patients with COPD and severe desaturation who were treated with supplemental oxygen.

A Woman with Lower Abdominal Pain

Posted by • October 27th, 2016

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Most ovarian abscesses that occur in patients in the Western world are associated with pelvic inflammatory disease and are preceded by involvement of the fallopian tube as part of an ascending bacterial infection. Direct extension from nongynecologic infections or hematogenous or lymphatic spread may occur less commonly. The absence of marked tubal involvement is uncommon. A 30-year-old woman presented to the hospital with abdominal pain, nausea, and chills. Evaluation showed tachycardia, bilateral lower-quadrant abdominal tenderness, leukocytosis, and an elevated CA-125 level. Imaging studies showed adnexal cysts. A diagnosis was made in a new Case Record article.

Clinical Pearl

Is abscess formation a common complication of endometriotic cysts?

Endometriosis and endometriotic cysts are commonly associated with a low-grade inflammatory response that is generally chronic. Acute inflammation with abscess formation is rare.

Clinical Pearl

What are some of the patient factors associated with an elevated CA-125 level?

As a large transmembrane glycoprotein derived from coelomic mesothelial cells (i.e., cells originating in the pericardium, pleura, or peritoneum) and müllerian epithelium (i.e., epithelium that lines the endometrium, endocervix, and fallopian tubes), CA-125 is a nonspecific marker for peritoneal inflammation. Many factors make an elevated CA-125 level unreliable for the screening and diagnosis of ovarian cancer, because many conditions can elevate the CA-125 level, and specific patient characteristics can raise and lower the level. For example, CA-125 levels are higher in premenopausal women and in women of African or Asian descent and lower in postmenopausal women, in women who smoke, and in women who have had a hysterectomy.

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Morning Report Questions

Q: How do isolated ovarian abscesses without tubal involvement differ from tubo-ovarian abscesses?

A: As compared with tubo-ovarian abscesses, ovarian abscesses without tubal involvement are frequently unilateral, with bilateral involvement present in only 20% of cases. In contrast to tubo-ovarian abscesses, which frequently involve the surface of the ovary, isolated ovarian abscesses are often unremarkable on the surface, and the abscess becomes apparent only on sectioning.

Q: What is known about the source of infection in cases of isolated ovarian abscesses?

A: An extensive body of literature exists regarding the types of infectious organisms associated with tubo-ovarian abscesses, with such abscesses attributed to Neisseria gonorrhoeae, Chlamydia trachomatis, mixed aerobic and anaerobic organisms that are reflective of normal vaginal or cervical flora, and, infrequently, mycobacteria. A less extensive body of literature exists regarding the causative agents in cases of isolated ovarian abscesses. Such cases have revealed a variety of causative organisms, including those found in the urinary, respiratory, or oropharyngeal and gastrointestinal tracts. A number of theories have been postulated with respect to the route of infection, including direct extension of a nongynecologic infection such as diverticulitis, appendicitis, or inflammatory bowel disease; hematogenous or lymphatic spread from a distant infection; and direct inoculation caused by procedural or operative manipulation of the ovary. Historically, the literature has focused on direct inoculation, with procedural and surgical manipulation being an obvious risk factor. Occasionally infection of a preexisting cyst may occur.

Public-Access Defibrillation and Out-of-Hospital Cardiac Arrest in Japan

Posted by • October 26th, 2016

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You are walking in a mall when you notice a crowd of people around a man lying unconscious on the ground. You run to him. No pulse. You start CPR (counting aloud, “1, 2, 3…”). You look around for an automated external defibrillator (AED) and see a bystander bringing it over. You pull off the man’s shirt, put the pads in place, and hear, “analyzing rhythm…shock advised.” You press the button. His body jumps and before restarting CPR, he begins to wake up. This is the ideal situation for public-access AEDs, but how many patients benefit from this intervention?

Early defibrillation with an AED is now a crucial part of prehospital care. Japan has been a leader in this movement. Since allowing citizens to use public-access AEDs in 2004, Japan has greatly increased the availability of these life-saving machines. In this week’s NEJM, Kitamura and colleagues expand on their previous assessment of the effect of widespread dissemination of public-access AEDs in Japan. Using nation-wide registry data, the investigators evaluated outcomes of out-of-hospital ventricular fibrillation cardiac arrest between 2005 and 2013 in patients who suffered a ventricular fibrillation arrest witnessed by bystanders, were treated by bystanders or emergency medical service (EMS), and were transferred to a medical institution. The primary outcome was one-month survival with favorable neurological outcome.

From 2005 to 2013, the number of public-access AEDs increased 40-fold from 10,961 to 428,821. Of the 43,762 patients with bystander-witnessed ventricular fibrillation arrest, 4499 (10.3%) received public-access defibrillation and 39,263 (89.7%) did not. The percentage of patients who received shocks from public-access AEDs for bystander-witnessed ventricular fibrillation arrest increased from 1.1% in 2005 to 16.5% in 2013 (P<0.001 for trend).

One-month survival in patients who received public-access defibrillation was 44.7%, versus 27.9% in those who did not receive public-access defibrillation (adjusted odds ratio, 1.66; 95% CI, 1.54-1.79). After controlling for confounding factors with propensity-score matching, a higher proportion of patients who received public-access defibrillation had favorable neurological outcomes than patients who did not (38.5% vs. 26.1%; adjusted OR, 1.99; 95% CI, 1.80-2.19). The absolute number of survivors with favorable neurological outcomes attributed to public-access defibrillation increased from 6 per year in 2005 to 201 per year in 2013 (P<0.001 for trend).

Studies based on registry data have several limitations. In this study, patients who received AED shocks had different baseline characteristics than patients who did not; they were less likely to be witnessed by a family member and more likely to receive bystander CPR. Additionally, the registry did not have data on failed AED attempts, AED location, and AED accessibility.

Overall, this study may inform public health policy. The results suggest that early public-access defibrillation, in addition to early CPR, can lead to better survival rates and neurological outcomes in out-of-hospital ventricular fibrillation cardiac arrests. However, a relatively small number of patients in the registry with ventricular fibrillation arrest benefited from the public-access AEDs. The authors argue that many factors could account for this finding, including the location and accessibility of AEDs, lack of CPR training, and inability of EMS dispatchers to inform bystanders of AED locations. Further cost-effectiveness analysis is needed to help guide public-access AED strategies and policies. John Jarcho, deputy editor at NEJM, adds, “This study demonstrates that increasing the number of public-access AEDs is not the only important step in improving the care of patients with out-of-hospital cardiac arrest.”

flanagan-ryanRyan Flanagan is an MD/MPH Candidate, Class of 2017, Tufts University School of Medicine