Portrait of a Stone: CT versus Ultrasonography for Acute Nephrolithiasis

Posted by Rena Xu • September 17th, 2014

This summer, I started my residency in urology. My job for the first month was to see patients in the emergency department with urologic problems. Nephrolithiasis was one of the most frequently encountered diagnoses, and I soon learned the “drill” for working up kidney stones– check a white blood cell count, send off a urinalysis and urine culture, and, almost reflexively, order a CT scan.

Was the CT scan a necessary first imaging test?  Or would many of those patients have been just as well off with an ultrasound instead, sparing them radiation while still leading us to the same diagnosis and treatment plan?

This week’s NEJM reports findings from a multi-center comparative effectiveness trial that examined how initial imaging affects outcomes for patients with suspected nephrolithiasis. The study randomly assigned over twenty seven hundred patients who’d presented to the emergency department with symptoms suggestive of kidney stones to one of three initial imaging modalities– point-of-care ultrasonography, performed by a provider in the emergency department; ultrasonography in the radiology department, performed by a radiologist; or an abdominal CT scan.  Providers could order additional imaging subsequently, as they deemed appropriate.  The main outcomes were the rate of high-risk diagnoses with complications that could be related to missed or delayed diagnoses (appendicitis with rupture, diverticulitis with abscess, bowel ischemia, pyelonephritis with urosepsis, and so on); cumulative radiation exposure over six months; and total cost.

There was no significant difference in the rate of high-risk diagnoses with complications across the three study arms (0.7% for point-of-care ultrasonography; 0.3% for radiology ultrasonography; and 0.2% for CT).  There was also no difference across the study arms in the percentage of patients who experienced serious adverse events.  But patients who underwent ultrasonography as the initial imaging modality were exposed to a lower cumulative dose of radiation than patients who underwent an initial CT scan (10.1mSv and 9.3 mSv for point-of-care and radiology ultrasonography, respectively, versus 17.2 mSv for CT scan; P<0.001).

“It should be emphasized…that ultrasonography when used alone is not very sensitive for detecting stones,” Dr. Gary Curhan of Brigham and Women’s Hospital in Boston writes in an accompanying editorial.  He also points out that whether a patient had a known history of kidney stones may have influenced the interpretation of ultrasonographic findings.  “It is possible that the characteristic shadowing or hydronephrosis would have been more likely to be reported in a patient with a history of stone disease, particularly if a recent imaging study had identified a stone.  This latter possibility is supported by the study’s findings that among persons in the ultrasonography groups, those with a history of nephrolithiasis were less likely than those without such a history to undergo subsequent CT.”  If a documented history of nephrolithiasis biased imaging interpretation, then the effectiveness of ultrasonography at making a correct diagnosis while “saving” patients from unnecessary radiation may be more limited than these study findings otherwise imply.

Time is another consideration.  In this study, patients assigned to ultrasound by a radiologist ended up spending more time in the emergency department than patients in either of the other groups (5.1 hours for point-of-care ultrasonography; 6.4 hours for radiology ultrasonography; and 6.2 hours for CT scan; P<0.001).  It is possible that the use of ultrasonography could result in delays in patient care.  And while the point-of-care ultrasonography group spent less time in the emergency department, over 40% of those patients ended up getting a CT scan (versus 27% of patients who underwent radiology ultrasonography).  In terms of cost, the average emergency room stay cost slightly less– $25 — for patients assigned to ultrasonography as compared to patients assigned to CT scan (the complete findings of the cost analysis were not reported in the paper).

After a diagnosis of stone disease has been made, management decisions may rely on information that can be obtained from CT but not from ultrasonography.  If surgical management is being considered, a CT scan is valuable for localizing the stones and planning an operative approach.  In addition, a CT scan may be more likely to identify additional stones that are not yet symptomatic, prompting a more aggressive regimen to prevent further stone formation.

As Curhan states, “Although we want to limit radiation exposure from all sources, the decision to use ultrasonography needs to be balanced against the additional information obtained by CT, which may influence subsequent clinical decisions.”

In your practice, do you routinely order CT scans for patients with suspected stone disease?  For which patients do you first order an ultrasound?  How will the findings of this study affect your approach to the diagnostic workup and management of nephrolithiasis?

Pancreatic Adenocarcinoma

Posted by Sara Fazio • September 12th, 2014

Cancer of the pancreas is predominantly adenocarcinoma and involves activating KRAS mutations in the large majority of cases. Surgical resection can be effective in localized disease; combination chemotherapy offers some palliation in advanced disease. A new review article on this topic comes from Massachusetts General Hospital’s David Ryan, Theodore Hong, and Nabeel Bardeesy.

Pancreatic ductal adenocarcinoma is the most lethal common cancer because it is usually diagnosed at an advanced stage and is resistant to therapy.

Clinical Pearls

•Describe the epidemiology of pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is rarely diagnosed in persons younger than 40 years of age, and the median age at diagnosis is 71 years. Worldwide, the incidence of all types of pancreatic cancer (85% of which are adenocarcinomas) ranges from 1 to 10 cases per 100,000 people, is generally higher in developed countries and among men, and has remained stable for the past 30 years relative to the incidence of other common solid tumors. It is the eighth leading cause of death from cancer in men and the ninth leading cause of death from cancer in women throughout the world. In the United States this year, pancreatic cancer is expected to develop in 46,000 people, and 40,000 people are expected to die from it. Although it is estimated that 5 to 10% of pancreatic cancers have an inherited component, the genetic basis for familial aggregation has not been identified in most cases.

Table 1. Risk Factors and Inherited Syndromes Associated with Pancreatic Cancer.

What is the most common oncogenic mutation in pancreatic adenocarcinoma?

One of the defining features of pancreatic adenocarcinoma includes a very high rate of activating mutations in KRAS (>90%). As the most common oncogenic mutation in pancreatic adenocarcinoma, KRAS activation has been investigated in depth for its contributions to the tumorigenic growth of established cancers. Several studies have shown that the KRAS mutation is a marker of a poor prognosis in both patients with resectable tumors and those with unresectable tumors. Functional studies have shown that KRAS is critical for the sustained growth of advanced pancreatic adenocarcinoma.

Morning Report Questions

Q: What clinical features are associated with pancreatic cancer, and what initial diagnostic tests are most important?

A: Approximately 60 to 70% of pancreatic cancers are located in the head of the pancreas, and 20 to 25% are located in the body and tail of the pancreas. The presenting signs and symptoms are related to the location. Patients with pancreatic cancer most commonly present with abdominal pain, weight loss, asthenia, and anorexia. Jaundice is a common manifestation of tumors in the head of the pancreas. Diabetes is present in at least 50% of patients with pancreatic cancer. Once a pancreatic mass is detected, abdominal computed tomography with both arterial and venous phases is usually sufficient to determine the initial stage and treatment. Pancreatic cancer metastasizes primarily to the liver, abdomen, and lungs. A biopsy of the pancreatic mass is most often accomplished by means of endoscopic ultrasonography. Although the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) have neither sensitivity nor specificity for use in screening to detect pancreatic cancer, if   elevated, they are useful in following patients with known disease.

Q: What is the prognosis of pancreatic cancer, and what treatment options are available for early stage disease?

A: More than 90% of patients who have received a diagnosis of pancreatic cancer die from the disease. Approximately 70% of these patients die from extensive metastatic disease; the other 30% have limited metastatic disease at the time of death, but many of them have bulky primary tumors. Surgical resection is the only potentially curative therapy for pancreatic cancer. A pancreaticoduodenectomy (the Whipple procedure) is required to remove tumors in the head and neck of the pancreas. Only 15 to 20% of patients are considered to be candidates for surgical resection, and many of these patients are found to have microscopically positive margins at the time of surgery. Adjuvant therapy includes systemic therapy to reduce the risk of distant metastases and chemoradiotherapy to reduce the risk of locoregional failure. A series of studies has established that 6 months of chemotherapy with either gemcitabine or fluorouracil, as compared with observation, improves overall survival. Although there is a clear consensus regarding the value of adjuvant chemotherapy, the role of adjuvant radiation therapy is controversial. Two European studies showed no benefit of adjuvant radiation therapy.

Figure 3. Anatomy and Surgical Resectability of Pancreatic Cancer. 

Table 2. Adjuvant Therapy for Pancreatic Cancer.

Rash, Headache, Fever, Nausea, and Photophobia

Posted by Sara Fazio • September 12th, 2014

In the latest Case Record of the Massachusetts General Hospital, a 39-year-old man was admitted to the hospital, 10 days after receiving prednisone for severe contact dermatitis, because of headache, nausea, and photophobia. Examination of the cerebrospinal fluid revealed white cells and gram-positive cocci. Diagnostic tests were performed.  The most common cause of bacterial meningitis in the United States is Streptococcus pneumoniae, a gram-positive coccus that is responsible for 58% of all cases.

Clinical Pearls

What is the classic presentation of and CSF findings associated with a diagnosis of acute bacterial meningitis?

Abrupt onset of fever and neck stiffness are classic symptoms of acute bacterial meningitis that are found on initial physical examination in 95% and 88% of cases, respectively. CSF analysis typical for bacterial meningitis includes an elevated white-cell   count with neutrophil predominance, hypoglycorrhachia (a low CSF glucose level), and an elevated total protein level. A white-cell count of more than 2000 per cubic millimeter or the presence of more than 1180 neutrophils per cubic millimeter in the CSF is nearly 100% specific for the diagnosis of bacterial meningitis, as is the finding of bacteria on Gram’s staining of the CSF.

What are the symptoms of chronic strongyloidiasis?

The intestinal nematode Strongyloides stercoralis is endemic in tropical and subtropical areas, such as the Dominican Republic, and can survive for decades in a single host because it can complete its life cycle inside the human body without passing into the environment. Patients with chronic strongyloidiasis often have fluctuating eosinophilia, intermittent abdominal pain, and recurrent rashes, the two most common of which are urticaria around the waist and buttocks and larva currens, a rapidly migrating serpiginous dermatitis. These symptoms develop as filariform larvae, the infectious form of Strong. stercoralis, initiate the autoinfection cycle by penetrating the perianal skin or the intestinal wall.

Figure 1. Life Cycle of Strongyloides stercoralis.

Morning Report Questions

Q: What is the strongyloides hyperinfection syndrome?

A: The strongyloides hyperinfection syndrome can develop in patients with chronic strongyloidiasis when host immune function is impaired. The stongyloides autoinfection cycle accelerates, which leads to more egg-laying adult nematodes in the intestine and a subsequent vast increase in the number of migrating larvae. The administration of glucocorticoids and, increasingly, the use of tumor-necrosis-factor inhibitors are major risk factors for the strongyloides hyperinfection syndrome (also called severe complicated strongyloidiasis); even short courses of these medications can cause overwhelming infection and death. Eosinophilia is usually absent during hyperinfection. In the most fulminant form of the strongyloides hyperinfection syndrome, called disseminated strongyloidiasis, filariform larvae can migrate to the liver, brain, kidneys, meninges, and skin. Furthermore, migrating filariform larvae can carry enteric bacteria into the bloodstream and also cause breaks in the intestinal mucosa that may provide a portal of exit for intestinal bacteria. As a consequence, bacterial sepsis, pneumonia, and meningitis are common complications of the strongyloides hyperinfection syndrome. Bacterial meningitis that occurs concurrently with the strongyloides hyperinfection syndrome is often caused by enteric gram-negative organisms.

Figure 1. Life Cycle of Strongyloides stercoralis. 

Q: How is the strongyloides hyperinfection syndrome diagnosed?

A: The diagnosis of the strongyloides hyperinfection syndrome can be made by examining the stool for filariform or rhabditiform larvae. This approach is not sensitive for the diagnosis of chronic strongyloidiasis, but during hyperinfection, a large number of larvae are present in the intestine, which improves the diagnostic yield of a stool sample.

Take the Case Challenge: A Man with Diarrhea, Nausea, and Weight Loss

Posted by Karen Buckley • September 11th, 2014

A 29-year-old man was seen in the walk-in clinic because of diarrhea of 1 year’s duration and weight loss. Initial laboratory values included elevated hepatic aminotransferase levels and a ferritin level of 1716 ng per milliliter. A diagnostic procedure was performed. What is the diagnosis? What diagnostic tests are indicated?

Read the case description. Then vote and comment about what the diagnosis may be and what diagnostic tests will prove useful. Find the answers in the full text of the case to be published on September 25.  Follow the conversation on Facebook and Twitter with #NEJMCases.



Posted by Sara Fazio • September 5th, 2014

Initial management for internal hemorrhoids includes adequate fiber and water intake and avoidance of straining. Office procedures (e.g., rubber-band ligation) are helpful when medical therapy fails; excisional therapies such as hemorrhoidectomy are used for severe disease.  Read the new Clinical Practice review article on this topic.

Symptoms related to hemorrhoids are very common in Western and other industrialized societies. Although published estimates of prevalence vary widely, millions of people in the United States are affected yearly.

Clinical Pearls

How are hemorrhoids categorized?

Hemorrhoids are categorized according to their origin relative to the dentate line, which is typically located about 3 to 4 cm proximal to the anal verge. The line represents the site where the squamous epithelial cells derived from the ectoderm interface with the columnar mucosa cells of endodermal origin. Besides being the basis for categorizing hemorrhoidal complexes as internal (if proximal to the dentate line), external (if distal to the dentate line), or mixed (both proximal and distal), the different embryonic origins lead to distinctly different vascular drainages, epithelialization, and innervation. Tissues that are distal to the dentate line are innervated by somatic nerves and are more sensitive to pain and irritation than those that are located more proximally, which receive sympathetic or parasympathetic visceral innervation.

Figure 1. Hemorrhoidal Disease. 

What are the typical clinical manifestations of symptomatic hemorrhoids?

The clinical manifestations of symptomatic hemorrhoids vary with the extent of the disease process. Patients who present for diagnosis and treatment typically report hematochezia (approximately 60%), itching (approximately 55%), perianal discomfort (approximately 20%), soiling (approximately 10%), or some combination of these symptoms. The rectal bleeding typically occurs with or immediately after defecation. Blood may be noticed on toilet paper, in toilet water, or, occasionally, staining the underwear. Patients should be queried about their fiber and fluid intake, bowel patterns (including stool frequency), bathroom habits (e.g., reading while seated on the toilet), the need for digital manipulation of prolapsed tissue, and whether there is a history of soiling or incontinence. Other disease processes must be considered. Substantial pain is rare in patients with uncomplicated internal or external hemorrhoids. The presence of severe pain raises the possibility of other conditions, including  anal fissure, perirectal or perivaginal infection, abscess, and other inflammatory processes, although severe pain may occur with  complications of hemorrhoids (e.g., prolapse with incarceration and ischemia or thrombosis).

Morning Report Questions

Q: What imaging is necessary in a patient with hemorrhoids?

A: Flexible endoscopy is not as successful as anoscopy for examining the anorectum. The decision to perform a more extensive colorectal evaluation should be informed by the patient’s age, presenting signs and symptoms and their duration, and the nature of bleeding. Evaluation of the entire colon is indicated for patients with any of the following: anemia; bleeding that is not typical of hemorrhoids; a change in bowel patterns; a personal history of rectal or colon polyps; a family history of inflammatory bowel disease, colorectal cancer, or other hereditary colorectal diseases in a first-degree relative; or other suspected pathologic pelvic changes that could contribute to the patient’s symptoms. For symptomatic patients younger than 50 years of age who have no risk factors for colonic disease and no evidence of other anorectal abnormalities and in whom examination confirms the presence of uncomplicated disease, hemorrhoid treatment can be administered in lieu of endoscopy or imaging studies. Persistent bleeding or other symptoms after successful local treatment of hemorrhoids is an indication for further evaluation.

Q: How should patients with symptomatic hemorrhoids be treated?

A: All patients should be encouraged to ingest a sufficient amount of insoluble fiber (typically 25 to 35 g per day) and sufficient water to avoid constipation and straining and to limit the time spent on the toilet. A meta-analysis of controlled trials showed that fiber supplementation was associated with significant reductions in the risk of persistent symptoms and the risk of rectal bleeding, although the effects of fiber supplementation on mucosal prolapse, pain, and itching were not significant. Clinical experience indicates that use of topical glucocorticoids, vasoconstrictors (e.g., phenylephrine-based creams or suppositories), or analgesics may provide temporary relief of some symptoms. For patients who do not respond to conservative treatment, a meta-analysis of 18 randomized trials comparing various treatment methods for grade I to III hemorrhoids concluded that rubber-band ligation was more effective than sclerotherapy and that patients who underwent ligation were less likely to need subsequent therapy. Rubber-band ligation was less effective than hemorrhoidectomy but had fewer complications and caused less pain. It therefore is considered appropriate as first-line therapy.

Influenza Vaccination in Pregnant Women

Posted by Sara Fazio • September 5th, 2014

In two trials of a trivalent inactivated influenza vaccine in pregnant women in South Africa, HIV-infected and HIV-uninfected vaccine recipients had increased influenza antibody titers and decreased influenza attack rates.

Pregnant women are designated as a priority group for seasonal influenza vaccination by the World Health Organization (WHO) because of their heightened susceptibility to severe influenza from the second trimester to the early postpartum period.

Clinical Pearls

What were the results of this study of trivalent inactivated influenza vaccine in the HIV-uninfected cohort?

The attack rates for confirmed influenza among placebo recipients and IIV3 recipients were 3.6% and 1.8%, respectively, indicating a vaccine efficacy of 50.4% (95% confidence interval [CI], 14.5 to 71.2). The vaccine efficacy was similar when determined according to the vaccine strain (46.1%; 95% CI, 6.4 to 69.0). For the 2 years of the study, the predominant strain of influenza virus circulating among placebo recipients was A/H3N2 (57.9%), for which an exploratory analysis identified a vaccine efficacy of 57.5% (95% CI, 7.6 to 80.4). The attack rate was lower among infants whose mothers were HIV-infected and HIV-uninfected  recipients (1.9%) than among those whose mothers were placebo recipients (3.6%), indicating a vaccine efficacy of 48.8% (95% CI, 11.6 to 70.4).

Table 4. Efficacy of IIV3 Vaccination in Mothers and Infants until 24 Weeks after Birth, Intention-to-Treat Population.

Figure 1. Kaplan-Meier Estimates of Percentages of Confirmed Cases of Influenza According to Cohort and Study Group.

What were the results of this study in the HIV-infected cohort?

In the cohort of HIV-infected mothers, the attack rate was lower among IIV3 recipients than among placebo recipients (7.0% vs. 17.0%), indicating an adjusted vaccine efficacy of 57.7% (95% CI, 0.2 to 82.1). The attack rates were 5.0% and 6.8% among infants of IIV3 recipients and infants of placebo recipients, respectively (vaccine efficacy, 26.7%; P=0.60). In 6 of 11 infants of HIV-infected mothers with confirmed influenza (55%), including 2 infants whose mothers received IIV3, the mothers were infected with the same strain as their infants.

Table 4. Efficacy of IIV3 Vaccination in Mothers and Infants until 24 Weeks after Birth, Intention-to-Treat Population.

Figure 1. Kaplan-Meier Estimates of Percentages of Confirmed Cases of Influenza According to Cohort and Study Group.  

Morning Report Questions

Q: What were adverse effects associated with vaccination?

A: Injection-site reactions (mainly mild to moderate) were more frequent among IIV3 recipients than among placebo recipients in both cohorts, but there were no other significant differences in solicited reactions between the two study groups in either cohort. There were no significant between-group differences with regard to rates of miscarriage, stillbirth, or premature birth or birth weight in the HIV-uninfected cohort and in the HIV-infected cohort. Among the HIV-infected cohort, IIV3 did not affect the plasma HIV-1 viral load, minimizing concern about the possibility of an increased risk of vertical transmission of HIV in vaccinees.

Table 1. Baseline Characteristics of HIV-Uninfected Pregnant Women, Fetal Outcomes, and Newborn Characteristics. 

Q: How did the influenza attack rate among HIV-infected and HIV-uninfected recipients who received placebo differ in this study, and what are the implications?

A: The authors note that the attack rate among HIV-infected placebo recipients in this study (17.0%) was greater than that observed among HIV-uninfected placebo recipients (3.6%), a finding that highlights the greater susceptibility of HIV-infected persons to influenza, even when the HIV infection is managed with antiretroviral treatment.

PARADIGM-HF: The Experts’ Discussion

Posted by Karen Buckley • September 4th, 2014

The PARADIGM-HF trial, presented last weekend at the European Society of Cardiology (ESC) Annual Congress and published in NEJM, suggests that neprilysin inhibition may replace ACE inhibition for the treatment of heart failure.  NEJM and ESC brought together the study co-chairs, John McMurray and Milton Packer, and cardiologists Mariell Jessup, Keith Fox, and Michel Komajda to discuss these practice-changing results in PARADIGM-HF- The Experts’ Discussion. View the video now on NEJM.org.

A new Perspective article includes an interactive timeline of select trials in heart-failure treatment since 1986. An accompanying editorial and concise video summary are also available on NEJM.org.

If you’re looking for further discussion on this topic, CardioExchange has an interview with the investigators, Will There Be a PARADIGM Shift in Treatment of Heart Failure?, and a critical assessment,  Let’s Take a Close Look at PARADIGM-HF, from Vinay Prasad.  NEJM JournalWatch Cardiology editor Harlan Krumholz also provides summary and comment.

Influenza Vaccination in Pregnancy

Posted by Rupa Kanapathipillai • September 3rd, 2014

As the days get shorter and cooler, you have an increasing sense of dread that Winter Is Coming – and with it comes flu season.   Once you stop daydreaming of the halcyon days of summer, you notice that in your waiting room are two pregnant patients, one HIV positive, one HIV negative.

You take a moment to reflect on how best to advise both patients regarding the approaching dreaded flu season. Do recommendations differ for the two women? What evidence are these recommendations based on?

Data on the efficacy and safety of vaccines in pregnant women are surprisingly limited, and they are even more limited in pregnant women who are HIV-infected.   Although pregnant women are at higher risk of severe influenza illness, especially from the second trimester of pregnancy until early post-partum, influenza vaccination rates in pregnancy were as low as 15%, but the rate has increased to about 50% since the 2009 H1N1 pandemic.   There may be tendency to feel that avoiding medical interventions, even vaccination, is safer for the developing fetus.  In this week’s NEJM, Dr. Madhi et al report the findings of two studies in HIV-infected and uninfected women in South Africa, seeking to provide some much-needed answers.

Two double-blind, randomized, placebo-controlled trials of trivalent inactivated influenza vaccines (IIV3) investigated the immunogenicity, safety and vaccine efficacy of IIV3 in pregnant HIV-infected and uninfected pregnant women and their infants in Soweto, South Africa.  The study included 2116 HIV uninfected and 194 HIV-infected pregnant women who were randomized to receive the IIV3 vaccine or placebo.  Outcomes of immunogenicity, safety, and vaccine efficacy were compared between the two arms.

The investigators found higher one-month seroconversion rates in HIV-infected and uninfected vaccine recipients and their newborns compared to placebo.  Significantly lower incidence of influenza illness was seen in HIV-uninfected vaccine recipients and their infants, with a vaccine efficacy of 50.4% [95%CI: 14.5% to 71.2%] and 48.8% [95%CI: 11.6% to 70.4%] respectively.  Among HIV-infected vaccine recipients, vaccine efficacy was 57.7% [95%CI: 0.2% to 82.1%].  Vaccine efficacy in HIV-exposed infants was 26.7% [p=0.60], but the study lacked sufficient power to detect a significant difference in HIV-exposed infants.  Higher proportions of HIV-infected and uninfected recipients experienced mild-moderate injection site reactions, but no other differences were found in rates of reactions or severe adverse events comparing vaccine recipients to non-recipients.

NEJM Deputy Editor Lindsey Baden states: ‘Protecting pregnant women and their infants from influenza infection and disease remains a high priority as these two groups are particularly vulnerable to severe complications from the flu. As the data from these studies show, influenza vaccination is a relatively simple way to achieve this.’

These data address key questions affecting this infrequently studied at-risk population and has significant public health implications.  Demonstration of vaccine efficacy and safety supports the recommendation of the World Health Organization, and should encourage clinicians to work for an increased uptake of influenza vaccination among pregnant women, including both HIV-infected and uninfected.

In your clinical practice, how do you counsel pregnant women regarding influenza vaccination?  What about HIV-infected pregnant women?  What questions do you have regarding vaccination during pregnancy in these populations? 

PARADIGM-HF Prompts a New Line of Thinking about Heart Failure

Posted by Chana Sacks • August 30th, 2014

Your patient – a 65-year-old man with an ischemic cardiomyopathy – presents to clinic one week after discharge from another hospitalization for a heart-failure exacerbation.

He is doing much better. He remains at his discharge weight and reports good adherence to a low-salt diet and to the extensive medication regimen that you have prescribed: he takes an aspirin, ACE inhibitor, beta-blocker, aldosterone antagonist, and a diuretic.  His ejection fraction is 30%, and he has NYHA class II heart-failure symptoms.

Doc, he asks you, are there any other medications I should be taking to keep me from getting hospitalized again or from dying from this?

His question has been the decades-long challenge facing physician-scientists working on heart failure.  Over the past quarter century, significant advances have been made. In 1987, the ACE-inhibitor enalapril was demonstrated to improve survival in patients with systolic heart failure [CONSENSUS].  In 1996, the mortality benefit of the alpha and beta-blocker carvedilol was shown [Packer], and in 1999, evidence of a mortality benefit with spironolactone added aldosterone antagonists [RALES] to heart-failure therapy.

With the PARADIGM-HF trial, published in this week’s NEJM, McMurray and colleagues report that a new drug can now be added to this list.  This study shows that the novel drug LCZ696 reduces mortality and decreases hospitalizations in patients with heart failure.

LCZ696 is a combination of the old angiotensin II receptor blocker (ARB) valsartan and the new neprilysin inhibitor sacubitril.   ARBs have long been used to replace ACE-inhibitors when patients cannot tolerate them, usually because of a cough.  Neprilysin is a neutral endopeptidase that degrades bradykinin, natriuretic peptides, and adrenomedullin.  Inhibition of neprilysin increases the circulating levels of those peptides.  According to the authors, these higher levels “counter the effects of neurohormonal overactivation that contributes to vasoconstriction, sodium retention and maladaptive remodeling.”

In this industry-funded, double-blind, randomized controlled trial of 8,000 patients, LCZ696 is compared with enalapril, a drug known to reduce mortality in heart failure. After a run-in period in which all screened participants received both drugs sequentially to ensure tolerance at target doses, patients were randomized to either LCZ696 at a dose of 200mg twice daily or enalapril 10mg twice daily.  Importantly, about 20% of screened participants were excluded during the run-in, most because of intolerance to one of the drugs.  Like your patient, all patients in the study had heart failure with an ejection fraction less than 40%.  Most were men, and they were well-managed medically at baseline, with more than 90% on a beta blocker, all on an ACE inhibitor (78%) or ARB (22%), and a majority on an aldosterone blocker.

The study was terminated early, after a median follow up of 27 months, because LCZ696 was found to be superior to enalapril, with a 20% reduction in the primary outcome of cardiovascular death or first hospitalization for heart failure (21.8% in the LCZ696 group compared with 26.5% in the enalapril group, P<0.0001).  All-cause mortality was also reduced, with 17% mortality in the LCZ696 group and 19.8% in the enalapril group (P <0.001). Overall, there was more symptomatic hypotension and non-serious angioedema in the LCZ696 arm, with more cough, renal failure, and hyperkalemia in the enalapril arm.

NEJM Executive Editor Greg Curfman describes the significance of this trial:  “Not only does this new treatment represent a significant advance, but it opens a new line of thinking about heart failure. Perhaps most exciting is the research it will stimulate in the future.”

In an accompanying editorial, Mariel Jessup, M.D., agrees, noting that the “PARADIGM–HF trial may well represent a new threshold of hope for heart failure patients.”

So to your patient – do you throw out his ACE inhibitor and start LCZ696?  Well, right now, you can’t.   LCZ696 is not FDA approved and is not commercially available.  Expect this study to form the basis of Novartis’ FDA application.  Perhaps by then it will have a catchier name.

Barrett’s Esophagus

Posted by Sara Fazio • August 29th, 2014

A new review article covers the epidemiology, pathogenesis, and natural history of Barrett’s esophagus and management options for the disorder.

It has been estimated that 5.6% of adults in the United States have Barrett’s esophagus, the condition in which a metaplastic columnar mucosa that confers a predisposition to cancer replaces an esophageal squamous mucosa damaged by gastroesophageal reflux disease (GERD). GERD and Barrett’s esophagus are major risk factors for esophageal adenocarcinoma, a deadly tumor whose frequency in the United States has increased by a factor of more than 7 during the past four decades. The metaplastic columnar mucosa of Barrett’s esophagus causes no symptoms, and the condition has clinical importance only because it confers a predisposition to cancer.

Clinical Pearls

How is the diagnosis of Barrett’s esophagus made?

The diagnosis of Barrett’s esophagus requires findings on endoscopy that columnar mucosa extends above the gastroesophageal junction, lining the distal esophagus, plus esophageal-biopsy results that confirm the presence of columnar metaplasia. Endoscopically, the gastroesophageal junction is identified as the most proximal extent of gastric folds, and the columnar mucosa is salmon-colored and coarse, in contrast to the pale, glossy esophageal squamous mucosa.

The extent of esophageal columnar metaplasia determines whether long-segment or short-segment Barrett’s esophagus (greater than or equal to 3 cm or <3 cm of columnar metaplasia, respectively) is diagnosed. However, authorities disagree on the histologic type of columnar mucosa that establishes a diagnosis of Barrett’s esophagus. U.S. gastroenterology societies require esophageal biopsies showing intestinal metaplasia with goblet cells (also called specialized intestinal metaplasia or specialized columnar epithelium) for a definitive diagnosis of Barrett’s esophagus. This intestinal metaplasia is a well-established risk factor for adenocarcinoma.

Figure 1. Diagnostic Features of Barrett’s Esophagus.

What are risk factors for Barrett’s esophagus as well as factors that may be protective?

Barrett’s esophagus is two to three times as common in men as in women, is uncommon in blacks and Asians, and is rare in children. Other important risk factors include obesity (with a predominantly intraabdominal fat distribution) and cigarette smoking, and there is a familial form of Barrett’s esophagus, which accounts for 7 to 11% of all cases. Most conditions associated with Barrett’s metaplasia are also risk factors for esophageal adenocarcinoma. Conversely, factors that might provide protection against Barrett’s esophagus include the use of nonsteroidal antiinflammatory drugs, gastric infection with Helicobacter pylori, and consumption of a diet high in fruits and vegetables.

Morning Report Questions

Q: What is the risk of esophageal adenocarcinoma in patients with nondysplastic Barrett’s esophagus?

A: Recent studies suggest that the risk of esophageal adenocarcinoma in the general population of patients with nondysplastic Barrett’s esophagus is only 0.1 to 0.3% per year. However, a number of factors influence the risk of cancer for individual patients. For example, cancer risk among men with Barrett’s esophagus is approximately twice that among women, the risk is greater with a longer segment of Barrett’s metaplasia, and the risk is especially high among persons with certain familial forms of Barrett’s esophagus. In addition, the risk appears to decrease with follow-up endoscopies showing no progression to dysplasia.

Q: How should Barrett’s esophagus be treated?

A: GERD should be treated aggressively in patients with Barrett’s esophagus, and there is indirect evidence to suggest that proton-pump inhibitors (PPIs) decrease the risk of cancer development. For example, a recent cohort study involving 540 patients with Barrett’s esophagus who were followed for a median of 5.2 years showed that PPI use was associated with a 75% reduction in the risk of neoplastic progression. Bile acids can also cause double-strand DNA breaks and might contribute to carcinogenesis in patients with Barrett’s metaplasia, and PPIs do not prevent bile reflux. Antireflux surgery can prevent reflux of all gastric contents (acid and bile), but the best available data suggest that surgery is not more effective than PPI therapy in preventing cancer. Thus, antireflux surgery is not advised solely for protection against cancer. Randomized, controlled trials have shown that endoscopic eradication of dysplasia in patients with Barrett’s esophagus with the use of photodynamic therapy or radiofrequency ablation (in which radiofrequency energy destroys the mucosa) significantly reduces the rate of progression to cancer. However, the efficacy of radiofrequency ablation for preventing cancer in patients with nondysplastic Barrett’s esophagus has not been established in long-term studies.