New Conversations on the NEJM Group Open Forum

Posted by Karen Buckley • December 18th, 2014

Will the results of the MR CLEAN trial change the standard of care for patients with acute ischemic stroke? Ask the authors and other experts in the field in the latest discussion about NEJM original research.

From the NEJM CareerCenter “Fascinating Physician” series, meet Dr. Wen Dombrowski, a geriatrics physician executive who develops technology, business, and collaborative health care solutions to improve the quality of life in vulnerable populations.

And the lively discussion with Dr. Julian Seifter on acid-base disorders has been extended for another week!

The NEJM Group Open Forum is publicly available for all to view, but in order to comment you must register with Medstro — a simple, one-minute process — and be a physician.

Where There’s Smoke: Cytisine versus Nicotine Replacement Therapy

Posted by Rena Xu • December 17th, 2014

Motivation, it’s often said, is half the battle of behavior change.  In the battle against nicotine addiction, however, motivation alone may not be enough.  Mass media campaigns have helped to raise awareness about the dangers of smoking.  But for the majority of smokers who already want to quit, the question remains: how?

In 2006, a drug called varenicycline — more commonly known as Chantix — entered the market.  Chantix is a partial agonist of nicotinic acetylcholine receptors; it works in part by decreasing the pleasure response to smoking.  In Eastern Europe, a related drug called cytisine has been used for smoking cessation for some time.  Cytisine has the same mechanism of action as Chantix but is sold as a generic agent and is much cheaper.  Both agents work differently from nicotine replacement therapy (e.g., gum or patches), which directly supply nicotine to the body.

A study published this week in NEJM compared the effectiveness of cytisine versus nicotine replacement therapy for smoking cessation.  1300 adult smokers in New Zealand were randomized to receive either cytisine for 25 days or nicotine replacement therapy for 8 weeks.  Participants also received behavioral support.  The primary outcome was self-reported continuous abstinence after one month.

At one month, 40% of participants in the cytisine group reported continuous abstinence, as compared to 31% of those on nicotine replacement therapy (absolute difference of 9.3 percentage points; 95% confidence interval 4.2 to 14.5; number needed to treat = 11).  Abstinence was also higher with cytisine than with nicotine replacement therapy at two and six months.  And, time to relapse (resumption of smoking) was longer for patients in the cytisine group as compared to the nicotine replacement group (53 versus 11 days; hazard ratio 0.8, P=0.001).

Not surprisingly, whether patients were compliant with therapy made a difference.  In the cytisine group, the median time to relapse was 127 days among compliant participants, versus only 20 days among those who were non-compliant (P<0.001).  Unfortunately, compliance rates weren’t great – only 53% in the cytisine group, and 67% in the nicotine replacement therapy group.

There were more self-reported adverse events with cytisine than nicotine replacement therapy, with an incidence rate ratio of 1.7 (P<0.001).  The most commonly reported events were nausea and vomiting and sleep disorders.  The authors note, “The higher proportion of adverse events in the cytisine group may be due to reporting bias, since the known side effects of nicotine-replacement therapy could have been regarded as ‘normal’ by participants in the nicotine replacement therapy group who had previously received such therapy and could therefore have gone unreported.”

Today, cytisine use is mostly limited to Eastern Europe.  Considering it is much less expensive than Chantix ($20-$30 for the recommended 25 day treatment course of cytisine versus $500 for 12 weeks of Chantix), if cytisine is indeed more effective than nicotine replacement therapy, as the findings of this study suggests, then introducing it to a broader market could yield tremendous value.

What is your current approach to smoking cessation?  What has been your experience with Chantix?  If cytisine becomes available to you, how do you anticipate it will fit into your treatment algorithm? 

For more on this topic, view the NEJM Quick Take animation, narrated by editor-in-chief Jeffrey Drazen.

Polycystic Kidney Disease

Posted by Carla Rothaus • December 11th, 2014

In patients with autosomal dominant polycystic kidney disease, the rate of increase in total kidney volume was not slowed by lisinopril and telmisartan, as compared with lisinopril and placebo, but was slowed with rigorous blood-pressure control.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by gradual cyst enlargement over a period of decades before the loss of kidney function. Hypertension occurs early and is associated with progression to end-stage renal disease (ESRD) and death from cardiovascular causes in patients with ADPKD. Immunohistologic studies and clinical studies support a central role of the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of hypertension in patients with ADPKD. It is unclear whether more aggressive antihypertensive therapy or an increased use of RAAS inhibitors delays progression to ESRD in patients with ADPKD.

Clinical Pearls

Does rigorous blood pressure control confer benefits in young patients with early ADPKD?

In the study by Schrier et al., as compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume, no overall change in the estimated GFR, a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion. Participants in the low-blood-pressure group had a 14.2% slower annual increase in total kidney volume, as compared with those in the standard-blood-pressure group (5.6% vs. 6.6%, P=0.006). Patients younger than 30 years of age with the largest kidneys were more likely to benefit from rigorous blood-pressure control than were patients of similar age with smaller kidneys. Men, but not women, also had evidence of a benefit from low blood pressure.

Figure 2. Changes in Total Kidney Volume and Estimated Glomerular Filtration Rate (eGFR) during Follow-up, and Subgroup Analyses, According to Blood-Pressure Group.

Is there a benefit to dual blockade of the RAAS in patients with autosomal dominant polycystic kidney disease?

Lisinopril-telmisartan treatment did not show a benefit, as compared with lisinopril alone, with regard to the change in total kidney volume or estimated GFR. The total kidney volume increased at similar rates in the lisinopril-telmisartan group and the lisinopril-placebo group (6.0% per year and 6.2% per year, respectively; P=0.52). Urinary albumin excretion remained unchanged in the two treatment groups. A significant and similar decline from baseline in the left-ventricular-mass index occurred in the two groups. Renal blood flow decreased and renal vascular resistance increased similarly in the two groups.

Figure 3. Changes in Total Kidney Volume and eGFR during Follow-up, and Subgroup Analyses, According to Treatment Group.

Morning Report Questions

Q: Were there significant between-group differences with respect to adverse events?

A: The proportion of patients with one or more episodes of dizziness and light-headedness at the end of the study was greater in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs. 69.4%, P=0.002). The frequencies of death, serious cardiovascular or renal events, hyperkalemia, acute kidney injury, and cancer did not differ significantly between the two groups. The proportion of patients who had one or more serious adverse events and symptoms was similar in the two groups.

Table 2. Adverse Events in the 2-by-2 Factorial-Design Trial.

Q: What do the authors conclude about the lack of improvement in the slope of the estimated GFR in cases where treatment decreased the rate of increase in total kidney volume?

A: A beneficial effect on cyst burden (rate of total kidney-volume growth) was not associated with an improvement in the slope of the estimated GFR. Whether a time lag between the therapeutic effect on total kidney volume and stabilization of the estimated GFR occurs in patients with ADPKD is not yet known. Given the combination of the decline in the estimated GFR in the short-term phase and a potential temporal delay between the change in total kidney volume and the change in the estimated GFR, this study was not of sufficient size or duration to show a potential benefit of blood-pressure control on kidney function.

Lactic Acidosis

Posted by Carla Rothaus • December 11th, 2014

When lactic acidosis accompanies low-flow states or sepsis, mortality rates increase sharply. A new review summarizes our current understanding of the pathophysiological aspects of lactic acidosis, as well as the approaches to its diagnosis and management.

Lactic acidosis results from the accumulation of lactate and protons in the body fluids and is often associated with poor clinical outcomes. The effect of lactic acidosis is governed by its severity and the clinical context. Mortality is increased by a factor of nearly three when lactic acidosis accompanies low-flow states or sepsis, and the higher the lactate level, the worse the outcome.

Clinical Pearls

What causes lactic acidosis?

Hyperlactatemia occurs when lactate production exceeds lactate consumption. In tissue hypoxia, whether global or localized, lactate is overproduced and underutilized as a result of impaired mitochondrial oxidation. Even if systemic oxygen delivery is not low enough to cause generalized hypoxia, microcirculatory dysfunction can cause regional tissue hypoxia and hyperlactatemia. Hyperlactatemia can also result from aerobic glycolysis, a term denoting stimulated glycolysis that depends on factors other than tissue hypoxia.  Activated in response to stress, aerobic glycolysis is an effective, albeit inefficient, mechanism for rapid generation of ATP. In the hyperdynamic stage of sepsis, epinephrine-dependent stimulation of the (beta)2-adrenoceptor augments the glycolytic flux both directly and through enhancement of the sarcolemmal Na+,K+-ATPase (which consumes large quantities of ATP). Other disorders associated with elevated epinephrine levels, such as severe asthma (especially with overuse of beta2-adrenergic agonists), extensive trauma, cardiogenic or hemorrhagic shock, and pheochromocytoma, can cause hyperlactatemia through this mechanism. Drugs that impair oxidative phosphorylation, such as antiretroviral agents and propofol, can augment lactic acid production and on rare occasions cause severe lactic acidosis. Cardiogenic or hypovolemic shock, severe heart failure, severe trauma, and sepsis are the most common causes of lactic acidosis, accounting for the vast majority of cases.

Table 1. Causes of Lactic Acidosis.

How is lactic acidosis diagnosed?

An elevated serum anion gap, particularly a value higher than 30 mmol per liter, can provide supportive evidence. However, other causes of a raised anion gap, such as ketoacidosis and toxic alcohol ingestion, should always be considered. A normal anion gap does not rule out lactic acidosis. In one study, 50% of patients with a serum lactate level of 5 to 10 mmol per liter did not have an elevated anion gap. Correction of the anion gap for the effect of serum albumin can improve its sensitivity, but many cases will still escape detection. Therefore, the serum anion gap lacks sufficient sensitivity or specificity to serve as a screening tool for lactic acidosis. An elevated blood lactate level is essential for confirmation of the diagnosis. Previously, the definition of lactic acidosis included a blood pH of 7.35 and a serum [HCO3-] of 20 mmol per liter or lower. However, the absence of one or both of these features because of coexisting acid-base disorders does not rule out lactic acidosis.

Morning Report Questions

Q: What general approaches should guide management of lactic acidosis?

A: Restoring tissue perfusion after hemodynamic compromise is essential in the treatment of patients with lactic acidosis. Vasopressors and inotropic agents should be administered as needed. Crystalloid and colloid solutions are both effective in restoring tissue perfusion in patients with sepsis or hypovolemia. Red-cell transfusions should be administered to maintain the hemoglobin concentration at a level above 7 g per deciliter. An adequate PO2 should be maintained by ensuring an appropriate inspired oxygen concentration, with endotracheal intubation and mechanical ventilation as needed. Given the potentially deleterious effects of an acidic environment, some clinicians recommend therapy with intravenous sodium bicarbonate for severe acidemia (blood pH, <7.2). However, the value of bicarbonate therapy in reducing mortality or improving hemodynamics remains unproven. Using dialysis to provide bicarbonate can prevent a decrease in ionized calcium, prevent volume overload and hyperosmolality (potential complications of bicarbonate infusion), and remove substances associated with lactic acidosis, such as metformin. Resuscitative efforts should be complemented by measures targeting the cause or causes of lactic acidosis.

Q: How should a patient be monitored for the development of lactic acidosis?

A: Measurement of the blood lactate level remains the cornerstone of monitoring for lactic acidosis. Lactate can be measured in arterial or venous blood, since the values are virtually interchangeable. An interval of 2 to 6 hours has been suggested for repeat lactate measurements, but this issue has not been examined rigorously. Changes in levels of blood lactate have been used to guide therapy. In a randomized, controlled study, a reduction of at least 20% in serum lactate levels every 2 hours was targeted for the first 8 hours of resuscitation; achievement of this target of lactate clearance was associated with decreased morbidity and mortality. Evidence that in seriously ill patients even lactate levels at the upper end of the normal range are associated with poor clinical outcomes argues for the normalization of blood lactate as a primary goal of therapy.

Table 2. Measures for Monitoring and Goals of Therapy in Patients with Lactic Acidosis.

Join the conversation on the NEJM Group Open Forum

Posted by Karen Buckley • December 9th, 2014

Two active conversations await your participation on the NEJM Group Open Forum, powered by Medstro, a social professional network for physicians.

Dr. Julian Seifter, author of the recent Review Article, “Integration of Acid-Base and Electrolyte Disorders,” is on hand to answer your questions on this topic.

Meet “Fascinating Physician” Andrey Ostrovsky, a Pediatrics Senior Resident at Boston Children’s Hospital whose numerous accomplishments include founding three companies and working as Health Policy Fellow to a US Senator. Ask him how he manages it all.

The forum is publicly available for all to view, but in order to comment you must register with Medstro — a simple, one-minute process. Look for two new discussions on December 18.

D Is for Delay

Posted by Carla Rothaus • December 5th, 2014

In the latest Clinical Problem-Solving article, a 47-year-old homeless man presented to the emergency department with intermittent pain and a pins-and-needles sensation in his legs. One month earlier, paresthesias had developed in his toes, which spread gradually to his shins.

Pellagra (or “rough skin,” from the Italian pelle agra) is rare in the United States, but it remains an important problem in developing countries. This condition results from inadequate dietary intake of niacin and is characterized by “the four Ds”: diarrhea, dermatitis, dementia, and death.

Clinical Pearls

What conditions or medications are associated with pellagra?

Pellagra may develop owing to malnutrition, food faddism, alcohol abuse, or medications such as isoniazid, pyrazinamide, fluorouracil, azathioprine, chloramphenicol, and ethionamide. In patients with HIV infection, pellagra-like manifestations such as dermatitis, diarrhea, and dementia can develop.

Describe the dermatitis associated with pellagra.

The dermatitis of pellagra involves sun-exposed skin in a bilateral and symmetric pattern. The characteristic and prominent eruption can occur on the dorsum of the hands, the V-area of the neck, the face, and exposed skin on the legs and feet. The rash may resemble a sunburn with erythema, or it may be characterized by hyperpigmentation, thickening, dryness, and roughness. Pain may also develop owing to fissures and excessive dryness. One of the hallmark clinical signs is an eruption on the front of the neck extending into the region of cervical dermatomes C3 and C4, simulating a necklace (Casal’s necklace).

Morning Report Questions

Q: What are some additional clinical features of pellagra?

A: Patients with pellagra can have a wide range of neuropsychiatric manifestations, such as irritability, anxiety, delusions, hallucinations, apathy, spastic paresis, fatigue, depression, myelitis, and peripheral neuropathy of the upper and lower extremities. Approximately half the patients with pellagra have gastrointestinal manifestations. Diffuse inflammation and atrophy of the mucosal surface of the gastrointestinal tract results in diarrhea. Anorexia and malabsorptive diarrhea lead to malnutrition and eventual cachexia.

Q: Is pellagra easy to recognize?

A: Although pellagra is a prototypical nutritional deficiency with a well-defined tetrad of clinical manifestations, it is not always easily recognized. The classic symptoms and signs of niacin deficiency typically evolve at different intervals over time, rather than appearing simultaneously, making it harder for the clinician to see the pattern.

Conduct Disorder

Posted by Carla Rothaus • December 5th, 2014

Children with repetitive rule-breaking, aggression, and disregard for others are at increased risk for substance abuse, educational disruption, and criminal behavior. Progress is being made toward understanding the clinical and neurocognitive features of youth conduct disorders.  Read the new review article on this topic.

The term “conduct problems” refers to a pattern of repetitive rule-breaking behavior, aggression, and disregard for others. Youth conduct problems are predictive of an increased risk of substance abuse, criminal behavior, and educational disruption; they also incur a considerable societal burden from interpersonal suffering and financial costs.

Clinical Pearls

When does youth conduct disorder present clinically?

For children with long-term behavioral problems, signs of conduct disorder often arise by early school age, but few children meet the full criteria for the disorder before 10 years of age. These early signs involve aggressive tendencies, impulsivity, and failure to comply with requests, which are features of attention deficit-hyperactivity disorder (ADHD) and oppositional-defiant disorder. Prospective data show a trajectory of behavioral problems, with progression from ADHD  behavioral problems in early school years to oppositional-defiant disorder in subsequent years, followed by conduct disorder as children approach adolescence. Although this developmental pattern is common, it is not typical in children who have early behavioral problems — that is, conduct disorder does not develop in most children with ADHD or oppositional-defiant disorder, and successful treatment of these two conditions may reduce the risk of progression.

Figure 1. Overlap among Six Clinical Entities.

What are features of youth conduct disorder with associated callous-unemotional traits?

Callous-unemotional traits, which occur in fewer than half of young persons with conduct disorder, identify a subgroup with distinctive clinical features and neurocognitive perturbations. As compared with youth with conduct disorder who show remorse, empathy, and concern about school performance, those with callous-unemotional traits have a poorer prognosis and treatment response. Like ADHD and oppositional-defiant disorder, callous-unemotional traits are expressed early. Such traits have been identified in children as young as 2 years of age, and among young children with conduct problems, they predict a particularly early onset of a severe, persistent variant of conduct problems. In youth with conduct disorder, the presence of callous-unemotional traits predicts a poor response to typical socialization practices.

Morning Report Questions

Q: What is the prognosis of youth conduct disorder?

A: Once the diagnosis of conduct disorder is established, the prognosis is usually considered to be poor, though the outcome varies. Antisocial personality disorder, which has a particularly poor prognosis, develops in slightly less than 50% of patients with conduct disorder; however, youth with conduct disorder in whom antisocial personality disorder does not develop typically have other long-term problems. Thus, persistent psychopathology is the rule, though its nature can vary.

Q: Are there effective treatments for youth conduct disorder?

A: Currently available treatments target symptoms rather than underlying mechanisms, since the latter are, as yet, unknown. Most important, currently available treatments are only moderately effective. Two types of psychosocial intervention are effective in reducing conduct problems. One targets diverse behaviors with the use of multiple treatment components, including components that rely on principles from cognitive behavioral therapy to address anxiety and related emotional problems. The other form of effective psychosocial intervention facilitates proper child-rearing practices. Two pharmacologic interventions also show promise, but concerns about adverse effects should lead to judicious use. First, antipsychotic medications reduce irritability and aggression in children, although the usefulness of these drugs is limited by short-term adverse effects, such as sedation, and long-term adverse effects from disrupted metabolic and neurologic functions. Second, data also show benefits of psychostimulant medications. In general, psychostimulants are preferable to antipsychotic agents owing to fewer adverse effects. Nevertheless, stimulants can exacerbate anxiety and cause agitation.

Delirium Tremens

Posted by Carla Rothaus • November 28th, 2014

Alcohol withdrawal syndromes are underdiagnosed and understudied. Prevention and treatment involve supportive care and administration of benzodiazepines.  A new review article on this topic comes from Dr. Mark A Schuckit at the University of California, San Diego, School of Medicine.

About 50% of persons with alcohol-use disorders have symptoms of alcohol withdrawal when they reduce or discontinue their alcohol consumption; in 3 to 5% of these persons, grand mal convulsions, severe confusion (a delirium), or both develop. Approximately 1 to 4% of hospitalized patients who have withdrawal delirium die.

Clinical Pearls

How can the severity of alcohol withdrawal be assessed, and what are the diagnostic criteria for delirium tremens?

The revised Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-Ar) is a withdrawal rating instrument that is commonly used by trained clinicians. Scores on the CIWA-Ar range from 0 to 67; scores lower than 8 indicate mild withdrawal symptoms that rarely require the use of medications, scores from 8 to 15 indicate moderate withdrawal symptoms that are likely to respond to modest doses of benzodiazepines, and scores higher than 15 indicate severe syndromes that require close monitoring to avoid seizures and alcohol withdrawal delirium. A patient who meets the criteria for both alcohol withdrawal and delirium is considered to have delirium tremens.

Table 1. Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised.

Table 2. DSM-5 Criteria for Withdrawal Delirium (Delirium Tremens). 

What factors are associated with the development of delirium tremens?

Delirium during alcohol withdrawal is predicted by the following: CIWA-Ar scores above 15 (especially in association with a systolic blood pressure >150 mm Hg or a pulse rate >100 beats per minute), recent withdrawal seizures (seen in 20% of persons with delirium), prior withdrawal delirium or seizures, older age, recent misuse of other depressant agents, and concomitant medical problems. The latter include electrolyte abnormalities (e.g., low levels of potassium, magnesium, or both), low platelet counts, and respiratory, cardiac, or gastrointestinal disease.

Morning Report Questions

Q: What are general guidelines for the management of withdrawal delirium?

A: The major treatment goals for withdrawal delirium are to control agitation, decrease the risk of seizures, and decrease the risk of injury and death; treatment is best carried out in a locked inpatient ward or an ICU [intensive care unit]. The approach to the management of withdrawal delirium includes a careful physical examination and appropriate blood tests to identify and treat medical problems that may have contributed to the severe withdrawal state. The same general types of support needed for any patient with delirium should be used for the patient with withdrawal delirium, including helping to reorient the patient to time, date, and place, evaluating and treating the patient in a well-lit room, providing reassurance, performing frequent monitoring of vital signs, and ensuring adequate hydration. Care should be taken when administering glucose to avoid precipitating Wernicke’s encephalopathy or thiamine-related cardiomyopathies and to circumvent overhydration in patients who have temporary, alcohol-related, compromised cardiac functioning.

Q: What is the mainstay of pharmacologic treatment for delirium tremens?

A: The mainstay of the pharmacologic treatment of withdrawal delirium is depressants such as benzodiazepines. No single drug of this class has been shown to be superior to another. The doses needed to control agitation and insomnia vary dramatically among patients and can be prodigious (e.g., >2000 mg of diazepam in the first 2 days in some patients); this underscores the advisability of providing treatment in a hospital, preferably in an ICU. Alternative depressant-like drugs have been proposed for uncomplicated withdrawal, but data are lacking regarding their use in persons who have withdrawal delirium.

Table 3. Suggested Treatment of Alcohol Withdrawal Delirium (Delirium Tremens).

Abdominal Aortic Aneurysms

Posted by Carla Rothaus • November 28th, 2014

Rupture of an abdominal aortic aneurysm is associated with a high risk of death. Endovascular repair results in lower perioperative morbidity and mortality than open repair, but the two methods have similar long-term mortality. The latest Clinical Practice review on this topic comes from Dr. K. Craig Kent at the University of Wisconsin School of Medicine and Public Health.

Rupture of an abdominal aortic aneurysm is often lethal; mortality is 85 to 90%. Of those persons who reach the hospital, only 50 to 70% survive. Thus, the goal is to identify and treat aneurysms before they rupture.

Clinical Pearls

What are the risk factors for abdominal aortic aneurysm?

Nonmodifiable risk factors for abdominal aortic aneurysm include older age, male sex, and a family history of the disorder. Starting at 50 years of age for men and 60 to 70 years of age for women, the incidence of aneurysms increases significantly with each decade. The risk of abdominal aortic aneurysm is approximately four times as high among men as among women and four times as high among people with a family history of the disorder as among those without a family history. Smoking is the strongest modifiable risk factor. Other, less prominent risk factors for abdominal aortic aneurysm include hypertension, an elevated cholesterol level, obesity, and preexisting atherosclerotic occlusive disease.

What are the recommendations for screening for abdominal aortic aneurysms?

Ultrasonography is the primary method used for screening and is highly sensitive (95%) and specific (100%). CT scanning and magnetic resonance imaging (MRI) are expensive, incur risks (radiation exposure from CT and risks associated with intravenous contrast material), and should not be used for screening but rather reserved for preinterventional planning. The current recommendations of the U.S. Preventive Services Task Force are a one-time screening in men 65 to 75 years of age who have ever smoked (grade B recommendation) and selective screening in men 65 to 75 years of age who have never smoked (grade C recommendation). Medicare also covers screening for patients with a family history of abdominal aortic aneurysm. Data from nonrandomized studies suggest that there may be subgroups of women who benefit from screening; however, this finding has not been prospectively validated.

Morning Report Questions

Q: What are the indications for surgical repair of an abdominal aortic aneurysm?

A: Under most circumstances, aneurysms should not be prophylactically repaired unless they are at least 5.5 cm in diameter. Nevertheless, there are occasions when repair of small aneurysms should be considered. Symptomatic aneurysms should be immediately repaired. Pain in the abdomen, back, or flank is the most common symptom, but aneurysms can produce many other symptoms or signs (e.g., hematuria or gastrointestinal hemorrhage). The rate of growth is another important predictor of rupture; aneurysms that expand by more than 0.5 cm in diameter over a period of 6 months should be considered for repair regardless of the absolute size. The observations that aneurysms rupture at a smaller size in women than in men and that women have higher rupture-related mortality than men have led some experts to recommend a diameter of 5.0 cm as the threshold for elective intervention in women. Other factors that are associated with an increased risk of rupture and may prompt repair at a threshold of less than 5.5 cm include the presence of a saccular aneurysm (most aneurysms are fusiform) and a family history of abdominal aortic aneurysm.

Table 1. Annual Risk of Rupture of Abdominal Aortic Aneurysms.

Q: What surgical techniques are available for repair of an abdominal aortic aneurysm?

A: Two approaches to repairing aneurysms are currently available: open repair (performed since the 1950s) and endovascular repair (first performed in 1987). Endovascular repair, a less invasive approach, involves the intraluminal introduction of a covered stent through the femoral and iliac arteries; the stent functions as a sleeve that passes through the aneurysm sac, anchoring in the normal aorta above the aneurysm and in the iliac arteries below the aneurysm. To be eligible for endovascular repair, a patient must have appropriate anatomy, including iliac vessels that are of sufficient size to allow introduction of the graft and an aortic neck above the aneurysm that allows the proximal graft to be anchored without covering the renal arteries. Thus, with existing techniques, there are some infrarenal aneurysms that are not amenable to endovascular repair. The use of endovascular repair has grown steadily in the United States, and this procedure is currently performed in more than 75% of patients undergoing surgical intervention for abdominal aortic aneurysm, with a portion of the remaining patients having unsuitable anatomy. Endovascular repair confers an initial survival benefit; however, this benefit disappears over a period of 1 to 3 years. Endovascular repair and open repair are associated with similar mortality over the long term (8 to 10 years).

Figure 1. Techniques Available for Repair of Abdominal Aortic Aneurysms.

Figure 2. Annual Proportion of Elective Endovascular and Open Repairs for Abdominal Aortic Aneurysms in the United States, 2000-2012.

Atenolol versus Losartan in Children and Young Adults with Marfan’s Syndrome

Posted by Daniela Lamas • November 25th, 2014

When French pediatrician Antoine-Bernard Marfan first described the syndrome that would bear his name in 1896, doctors knew little about the management and prognosis of the connective tissue disorder.

In the century since that first description, what was once a fatal syndrome due to the risk of aortic dissection is now a condition that can be managed with proper care and follow-up. Two decades ago, a trial demonstrated that patients who were given beta blockade with propranolol had a lower rate of aortic enlargement than those given placebo, ushering in the beta blocker as a key component of therapy for those with Marfan’s.

More recently, basic science research into the pathogenesis of the disease has led to a new management strategy using angiotensin receptor blockade in lieu of beta blockade. Now, a study in this week’s issue of NEJM adds to this body of research, suggesting that one treatment modality might be no better than the other.

The science behind this trial dates back to the early 1990s, when researchers discovered that mutations in the gene encoding a protein called fibrillin-1 were responsible for Marfan’s syndrome. Fibrillin-1 is a structural component of elastic fibers in connective tissue, and also influences cell signaling activity through binding the protein TGF beta. Animal studies have provided evidence that excessive TGF beta signaling results in the clinical findings of Marfan’s, including aortic dilatation. This finding led to the question – could angiotensin receptor blockers (ARBs), which inhibit TGF beta signaling, reduce aortic dilatation in Marfan’s?

This hypothesis first led to mouse studies, which did in fact show a reduced rate of aortic enlargement in Marfan’s mice who received losartan, an ARB, compared to those who were given beta blockers or placebo. A small series of patients and then two clinical studies comparing a beta blocker-ARB combination to beta blockade alone came to similar conclusions.

With this background, R.V. Lacro and colleagues set out to determine whether losartan is more effective than beta-blockers in slowing aortic-root enlargement in Marfan’s syndrome. The investigators enrolled just over 600 patients with Marfan’s whose ages ranged from 6 months to 25 years old. The study participants were randomly assigned to receive either atenolol or losartan. They were followed over a 3-year period for the primary outcome, which was the rate of aortic-root enlargement. Investigators also monitored rates of aortic-root surgery, aortic dissection and adverse events.

Their findings were surprising, given the strong rationale for treatment with an ARB in this population. In all of the endpoints studied, the investigators found that losartan performed no better than atenolol. There was no significant difference between groups in the rate of aortic-root enlargement, nor in rates of surgery, dissection or death.

What to take from this study?  In an accompanying editorial, Juan Bowen and Heidi Connelly discuss certain limitations of the study design that might have masked the true benefit of losartan for Marfan’s syndrome and urge physicians, instead of casting aside losartan as a therapeutic option, to “wait and see.” First, the editorialists note, the study did not have a placebo group and thus, cannot address the question of whether both beta-blockade and angiotensin-receptor blockade might be equally effective. The study also did not assign patients to a combined beta and angiotensin receptor blockade group, which could have demonstrated synergistic effects. Additionally, the losartan dose might not have been sufficient to meet its goal – suppressing TGF beta signaling. Finally, the enrolled patients had “advanced aortic disease” as gauged by their aortic root dilation scores at young ages. Perhaps, they note, blocking TGF beta could work more effectively at earlier disease stage.

Despite the study’s limitations, Bowen and Connelly write that they expect these results to stimulate debate and further research into how best to treat patients with Marfan’s. They conclude, “Each step forward gives hope to those living with Marfan’s syndrome as they strive to live healthier, longer, and more productive lives.”