Diagnosing One Letter at a Time

Posted by Carla Rothaus • January 2nd, 2015

A 45-year-old woman presented with lower-extremity weakness. She first noted weakness in her ankles and feet 5 months previously. The weakness progressed to involve her knees and hips, and she had been unable to walk without support for the prior 2 months.

Electrodiagnostic studies cannot always classify a neuropathy definitively into an axonal or demyelinating category; in such cases, history and examination are essential in interpreting the results.

Clinical Pearls

What is the POEMS syndrome?

The POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome is a rare paraneoplastic syndrome associated with a monoclonal plasma-cell dyscrasia. The pathophysiology of the POEMS syndrome is not fully understood, but the overproduction of proinflammatory and proangiogenic cytokines appears to play a major role in the disorder; in particular, there is marked overproduction and secretion of VEGF [vascular endothelial growth factor] by plasma cells. VEGF-induced neovascularity and microvascular permeability are postulated to cause most of the hallmark manifestations of this syndrome. Interleukin-12 is also overproduced in the POEMS syndrome and may play a role in the pathogenesis of the disorder. Sclerotic bone lesions or Castleman’s disease (a rare lymphoproliferative disorder) are present in nearly all patients with the POEMS syndrome. The disease course is chronic and progressive, with a reported median survival of 13.8 years.

What are the diagnostic criteria for the POEMS syndrome?

The diagnosis of the POEMS syndrome requires evidence of a polyneuropathy and a monoclonal plasma-cell proliferative disorder, as well as at least one other major criterion and one minor criterion.

Table 2. Proposed Diagnostic Criteria for the POEMS Syndrome.

Morning Report Questions

Q: Can electrodiagnostic testing distinguish between POEMS syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP)?

A: A terminal latency index of 0.38 or more, indicating comparatively less distal demyelination, has good sensitivity and specificity for distinguishing the POEMS syndrome from the more common CIDP. Patients with the POEMS syndrome usually have uniform demyelination, whereas patients with CIDP tend to have multifocal demyelination that is more severe in the proximal and distal nerve segments.

Q: How is the POEMS syndrome treated?

A: Treatment for the POEMS syndrome is guided by findings from observational studies in the absence of data from randomized, controlled trials. For patients who have plasmacytoma (or plasmacytomas) without bone marrow involvement, radiation therapy to affected sites alone may be curative. However, patients with clonal plasma cells on bone marrow biopsy require treatment with systemic chemotherapy. Patients treated with glucocorticoids in conjunction with an extended course of melphalan have had symptomatic benefit (with improvement initially in fluid overload and later in neuropathy) and reduced mortality, as compared with patients treated with either glucocorticoids alone or limited courses of alkylator-based chemotherapy. Case series of patients treated with high-dose melphalan conditioning followed by autologous peripheral-blood stem-cell transplantation have had long-lasting and clinically significant improvements in symptoms and hematologic and radiologic findings and have had normalization of plasma VEGF levels, with a 5-year overall survival rate of 94%. Case series or reports have also suggested favorable outcomes with the use of thalidomide, lenalidomide, or bortezomib-based therapies in patients who are too ill to undergo stem-cell transplantation or who have disease that is refractory to other therapies.

Disorders of Plasma Sodium

Posted by Carla Rothaus • January 2nd, 2015

The latest review in the Disorders of Fluids and Electrolytes series considers the causes and consequences of an abnormal plasma sodium concentration and offers a framework for correcting it.

Human cells dwell in salt water. Their well-being depends on the ability of the body to regulate the salinity of extracellular fluids. By controlling water intake and excretion, the osmoregulatory system normally prevents the plasma sodium concentration from straying outside its normal range (135 to 142 mmol per liter). Failure of the system to regulate within this range exposes cells to hypotonic or hypertonic stress.

Clinical Pearls

What factors determine plasma sodium concentration, and how does plasma sodium concentration affect cell volume?

Solute concentrations (osmolalities) must be equal inside and outside of cells because water channels (aquaporins) make cell membranes permeable to water. Although sodium is largely extracellular and potassium is intracellular, body fluids can be considered as being in a single “tub” containing sodium, potassium, and water, because osmotic gradients are quickly abolished by water movement across cell membranes. As such, the concentration of sodium in plasma water should equal the concentration of sodium plus potassium in total body water.

Plasma [Na+] = total body (Na+ + K+)/total body H20.

This concentration is altered by net external balances (intake minus output) of sodium, potassium, and water and by internal exchange between sodium that is free in solution and sodium that is bound to polyanionic proteoglycans in bone, cartilage, skin, and connective tissue. The term “tonicity” describes the effect of plasma on cells — hypotonicity makes cells swell and hypertonicity makes them shrink. Hypernatremia always indicates hypertonicity. Hyponatremia usually indicates hypotonicity, but there are exceptions.

Figure 1. Internal and External Solute and Water Balance and the Plasma Sodium Concentration.

What determines the tonicity of urine, and is urinary sodium excretion linked to plasma sodium concentration?

The electrolyte concentration (sodium plus potassium) of urine, and not its osmolality (which includes electrolytes, urea, and glucose), determines its effect on the plasma sodium concentration. Urine is hypotonic if its electrolyte concentration is lower than that of plasma; because it is partly composed of electrolyte-free water, it will increase plasma sodium concentrations. Conversely, urine is hypertonic if its electrolyte concentration is higher than that of plasma; its excretion will lower plasma sodium concentrations. Urinary excretion of sodium is relatively independent of plasma sodium levels. Excretion of sodium responds to intravascular volume, increasing with volume expansion and decreasing with volume depletion.

Morning Report Questions

Q: What are general guidelines for the management of hyponatremia?

A: Hyponatremia is usually a chronic condition; to reduce symptoms and improve potential outcomes, it should be corrected gradually with the use of fluid restriction, salt tablets, slow infusions of 3% saline, furosemide, urea, or vasopressin antagonists, or by treatment of the underlying cause. Even when symptoms are severe, chronic hyponatremia need not be corrected by increasing the plasma sodium concentration by more than 4 to 6 mmol per liter per day. Regardless of how chronic hyponatremia is treated, inadvertent overcorrection, most commonly caused by excretion of dilute urine, is common and can be very dangerous. If the plasma sodium concentration is less than 120 mmol per liter, or if there are risk factors for osmotic demyelination, correction of the plasma sodium concentration by more than 8 mmol per liter per day should be meticulously avoided through replacement of lost water or prevention of water loss with desmopressin, a synthetic vasopressin.

Table 1. Treatment and Limits of Correction of Severe Hyponatremia.

Table 2. Treatment and Limits of Correction of Severe Hypernatremia.

Q: What are the consequences of rapid changes in plasma sodium concentration?

A: Although osmotic disturbances affect all cells, clinical manifestations of hyponatremia and hypernatremia are primarily neurologic, and rapid changes in plasma sodium concentrations in either direction can cause severe, permanent, and sometimes lethal brain injury. If severe hypernatremia develops over a period of minutes (e.g., after massive ingestion of salt that may occur in a suicide attempt), vascular injury created by a suddenly shrinking brain causes intracranial hemorrhage. Brain swelling from an abrupt onset of hyponatremia results in increased intracranial pressure, impairing cerebral blood flow and sometimes causing herniation. Brain injury after rapid correction of chronic hyponatremia manifests as a biphasic illness called the osmotic demyelination syndrome: an initial reduction in symptoms is followed by a gradual onset of new neurologic findings. The clinical spectrum of the osmotic demyelination syndrome is broad and can include seizures, behavioral abnormalities, and movement disorders. The most severely affected patients become “locked in,” unable to move, speak, or swallow because of demyelination of the central pons. Acute hypernatremia may also cause brain demyelination, without the biphasic clinical course of the osmotic demyelination syndrome.

Figure 3. Consequences of Rapid Changes in the Plasma Sodium Concentration.

Intraarterial Treatment for Acute Ischemic Stroke

Posted by Chana Sacks • December 31st, 2014

She knew the signs.

When Mary suddenly dropped her coffee cup because all of the strength in her right arm disappeared and her speech became garbled, she knew that she was having a stroke.  A wise 78-year-old, Mary couldn’t remember where she had learned these warning signs – was it from from her doctor? A friend? Something on TV? – but she realized that she had to get to a hospital.  Her husband called 9-1-1, and she was transported to the Emergency Department.

Suspecting that Mary was correct in the diagnosis, the Emergency Department physician urgently paged the neurology team, while rushing her into the CT scanner. A non-contrast head CT showed no intracranial bleed, and less than 90minutes after the onset of her first symptom, thrombolytics were pushed through the IV in her arm.  A CT angiogram ultimately confirmed that an occlusion in the middle cerebral artery was indeed the culprit.  While the care Mary had received up to this point had been efficient and consistent with the latest evidence, the question remained: could anything else be done to improve her chance of a good functional outcome?

This was precisely the question that the MR CLEAN investigators posed in a new trial of intraarterial treatment, now published in NEJM.   Prior to this study, intravenous alteplase administered within 4.5 hours of stroke onset was the only proven effective reperfusion therapy for acute ischemic strokes. The MR CLEAN researchers sought to examine whether intraarterial treatment – defined as intraarterial thrombolysis, mechanical thrombectomy, or both – improved outcomes. The data from this trial offer reasons to believe that we may be entering a new era in the treatment of acute ischemic strokes.

This phase 3 trial included 500 adults from 16 centers in the Netherlands who were randomized to either usual care plus intraarterial treatment or usual care alone.  All participants had an acute ischemic stroke caused by a proximal occlusion of the anterior cerebral circulation demonstrated on vessel imaging, had a score of 2 or greater on the NIH Stroke Scale, and could undergo intraarterial treatment within 6 hours of stroke onset.   Importantly, usual care could include the use of intravenous thrombolytics, and 89% of patients received IV alteplase prior to randomization.   The mean age of participants in the trial was 65 years.  There was no upper age limit, and in fact, the oldest patient in the study was 96.

The data show a significant improvement in functional outcomes for participants in the intraarterial treatment arm: at 90 days, 32.6% of participants in the intervention arm were functionally independent (with a score of 2 points or less on the modified Rankin that measures functional outcomes) as compared with 19.1% in the usual care arm [absolute difference 13.5 percentage points, 95% CI 5.9 to 21.2].  No significant difference was observed in the rates of mortality or symptomatic intracranial hemorrhage.  However, at 90 days, 13 of 233 patients (5.6%) in the intraarterial treatment group had signs of a new ischemic stroke in a different vascular territory, as compared with only 1 of 267 patients (0.4%) in the control arm.

In an accompanying editorial, Dr. Werner Hacke poses the critical question.  He asks, “Is there any doubt left, or should thrombectomy now become the new standard treatment for severe stroke with proximal large-vessel occlusion up to 6 hours after stroke onset?” In the end, he seems cautiously optimistic but suggests that further data will be critical. Putting it all in context, he calls this trial, “the first step in the right direction.”

Back to Mary – as intraarterial treatment is not currently the standard of care, it seems likely that the hospital where she presented will hope that IV thrombolysis is enough to restore her highly functional baseline.  However, if further trials that are already underway confirm the results found here, we may soon be able to do more to stave off the potentially devastating effects of large ischemic strokes.

For more on MR CLEAN, view the Quick Take video summary.

Esophageal Carcinoma

Posted by Carla Rothaus • December 26th, 2014

The 5-year survival rate in esophageal cancer, although poor, has improved over the past decade. A new review discusses the epidemiologic aspects, pathogenesis, prevention, and therapy of esophageal adenocarcinoma and squamous-cell carcinoma, focusing on recent advances.

In spite of the fact that the ability to detect early-stage esophageal adenocarcinoma has improved, most tumors are found when regional metastasis (in 30% of cases) or distant metastasis (in 40% of cases) has already occurred, at which point the 5-year survival rate declines from 39% in cases of localized disease to 4% in cases with distant metastasis.

Clinical Pearls

Describe the epidemiology of esophageal cancer.

Esophageal cancer has two main subtypes — esophageal squamous-cell carcinoma and esophageal adenocarcinoma; their precursor lesions are esophageal squamous dysplasia and Barrett’s esophagus, respectively. Although squamous-cell carcinoma accounts for about 90% of cases of esophageal cancer worldwide, the incidence of and mortality rates associated with esophageal adenocarcinoma are rising and have surpassed those of esophageal squamous-cell carcinoma in several regions in North America and Europe. In the United States, more than 18,000 new cases of esophageal cancer and more than 15,000 deaths from esophageal cancer were expected in 2014. Esophageal carcinoma is rare in young people and increases in incidence with age, peaking in the seventh and eighth decades of life. The main risk factors for esophageal adenocarcinoma are gastroesophageal reflux disease, obesity, and cigarette smoking; H. pylori infection is associated with a reduced risk. Cigarette smoking and alcohol consumption constitute the main risk factors for esophageal squamous-cell carcinoma. High intake of red meats, fats, and processed foods is associated with an increased risk of both types of esophageal cancer, whereas high intake of fiber, fresh fruit, and vegetables is associated with a lower risk.

How do esophageal adenocarcinoma and esophageal squamous-cell carcinoma differ?

Esophageal adenocarcinoma has become the predominant type of esophageal cancer in North America and Europe, while esophageal squamous-cell carcinoma remains the predominant esophageal cancer in Asia, Africa, and South America and among African Americans in North America. Adenocarcinoma is three to four times as common in men as it is in women, whereas the sex distribution is more equal for squamous-cell carcinoma. The endoscopic appearance is also similar, although approximately three quarters of all adenocarcinoma lesions are found in the distal esophagus, whereas squamous-cell carcinoma is more frequent in the proximal to middle esophagus. The overall 5-year survival rate for patients with esophageal adenocarcinoma in the United States is approximately 17%, which is slightly higher than the rate for patients with squamous-cell carcinoma.

Morning Report Questions

Q: What is the typical presentation of a patient with esophageal carcinoma?

A: The clinical presentation is similar between esophageal adenocarcinoma and squamous-cell carcinoma, despite differences in demographic and risk factors. Common clinical presentations include progressive dysphagia, weight loss, and heartburn unresponsive to medical treatment, as well as signs of blood loss. Less common symptoms include hoarseness, cough, and pneumonia related to laryngeal nerve paralysis or invasion of the tracheobronchial tree.

Q: How is adenocarcinoma of the esophagus treated?

A: The introduction of endoscopic mucosal resection with or without ablation has been a major advance in treating not only Barrett’s esophagus with high-grade dysplasia but also adenocarcinoma that is limited to the epithelial portion of the mucosa (category T1a), particularly for small tumors (<2 cm in diameter) that are asymptomatic and noncircumferential. In patients with category T1b tumors that have penetrated the muscularis mucosae and entered the submucosa, the risk of lymph-node spread is as high as 20%, and radical esophagectomy may be the preferred method of treatment, although some treatment centers have expanded the indications for endoscopic therapy to include low-risk submucosal tumors. Locally advanced tumors, defined as category T3N1, are best treated with esophagectomy. The main advance in treating patients who undergo esophagectomy has been the adoption of neoadjuvant treatment.       Randomized, controlled trials have shown a survival benefit with neoadjuvant chemoradiotherapy or chemotherapy, as compared with esophagectomy alone, in both types of esophageal carcinoma. Obstructive symptoms related to unresectable disease can be palliated with endoscopic esophageal stenting or high-dose intraluminal brachytherapy.

Figure 2. Simplified Staging of Esophageal Carcinoma.

Table 1. Management of Esophageal Adenocarcinoma.


Acute Traumatic Brain Injury

Posted by Carla Rothaus • December 26th, 2014

In a phase 3 trial, progesterone had no benefit as a neuroprotective agent in patients with blunt traumatic brain injury. Together with a second negative clinical trial of progesterone for acute TBI (SYNAPSE), the findings provide no support for this therapeutic approach.

More than 2.4 million emergency department visits, hospitalizations, or deaths are related to traumatic brain injury (TBI) annually, and approximately 5.3 million Americans are living with disability from TBI. The aggregate annual cost of TBI in the United States now approaches $76.5 billion. Survivors of severe TBI typically require 5 to 10 years of intensive therapy and are often left with substantial disability. Despite decades of research, no pharmacologic agent has been shown to improve outcomes after TBI.

Clinical Pearls

What is the basis for interest in the use of progesterone for acute traumatic brain injury?

Progesterone is a potent neurosteroid synthesized in the central nervous system. Preclinical studies in laboratory animals indicated that the early administration of progesterone after experimental TBI reduced cerebral edema, neuronal loss, and behavioral deficits. Enthusiasm for progesterone as a treatment for TBI was further stimulated by two single-center clinical trials showing decreased mortality and improved functional outcomes with progesterone as compared with placebo.

•What do the Extended Glasgow Outcome Scale (GOS-E) scores indicate with respect to functional outcome?

A GOS-E score of 1 indicates death, 2 indicates a vegetative state, 3 or 4 indicates severe disability, 5 or 6 indicates moderate disability, and 7 or 8 indicates good recovery.

Q: Does the early administration of progesterone (within 4 hours after injury) improve the outcome in patients with moderate-to-severe acute TBI when compared to placebo?

A: Despite extensive preclinical data and two promising single-center trials, progesterone was not associated with any benefit over placebo, as measured by the GOS-E score at 6 months, in this large, multicenter clinical trial. For the primary hypothesis comparing progesterone with placebo, favorable outcomes occurred in 51.0% of patients assigned to progesterone and in 55.5% of those assigned to placebo; the model estimated a relative benefit of 0.95 (95% confidence interval [CI], 0.85 to 1.06; P=0.35), with a relative benefit of less than 1.00 indicating fewer favorable outcomes in the progesterone group than in the placebo group.

Table 2. Outcomes at 6 Months.

Q: Was progesterone associated with more adverse events than placebo in this trial?

A: Progesterone was associated with an acceptable safety profile. Eight prospectively defined adverse events that were deemed to be potentially associated with the study drug were similar in frequency in the two groups. However, phlebitis or thrombophlebitis was significantly more frequent in the progesterone group than in the placebo group (relative risk, 3.03; 95% CI, 1.96 to 4.66). Episodes of phlebitis were frequently categorized as not serious and were self-limited.

Table 3. Adverse Events Potentially Associated with the Study Drug. 

Two New NEJM Quick Takes – Watch them Now!

Posted by Karen Buckley • December 22nd, 2014

The latest Quick Take animation, narrated by Editor-in-Chief Jeffrey Drazen, summarizes a new study that explores the efficacy of a not-so-new but largely unknown over-the-counter medication for smoking cessation. In the randomized trial of smokers who called New Zealand’s national Quitline, cytisine (a partial nicotinic acetylcholine receptor agonist) was superior to nicotine-replacement therapy in helping smokers quit. Would this less expensive treatment work elsewhere in the world? View the Quick Take on smoking cessation.  For more information, read the full article, and the Insights post on this topic.

A new Quick Take video summary gives an overview of the recently published results of the MR CLEAN trial, which found that for patients with acute ischemic stroke caused by a proximal occlusion of the anterior circulation, intra-arterial therapy administered within six hours of symptom onset can improve functional outcomes. Watch the video summary now. For more information, read the full article and accompanying editorial. And to discuss the results with the authors and experts in the field, participate in the live discussion on the new NEJM Group Open Forum.

You may also wish to peruse previous Quick Takes you may have missed.

Acute Pericarditis

Posted by Carla Rothaus • December 19th, 2014

Acute pericarditis in the United States is usually idiopathic and presumed to be viral. A history and laboratory tests, a chest radiograph, and an echocardiogram are used in evaluation. Treatment usually includes an NSAID and colchicine.  The latest Clinical Practice review, on this topic, comes from Dr. Martin LeWinter, at the University of Vermont Medical Center.

In developed countries, roughly 80 to 90% of cases of acute pericarditis are idiopathic; that is, no specific cause is identified after routine evaluation. It is assumed that these cases are viral. The remaining 10 to 20% of cases are most commonly associated with post-cardiac injury syndromes, connective-tissue diseases (especially systemic lupus erythematosus), or cancer.

Clinical Pearls

How does acute pericarditis present clinically, and what are the diagnostic criteria?

Chest pain is the presenting symptom in virtually all patients for whom a diagnosis of pericarditis would be considered. Although the differential diagnosis of chest pain is extensive, certain features point strongly to pericarditis, especially pleuritic pain that is relieved by sitting forward and that radiates to the trapezius ridge (the latter feature is virtually pathognomonic). Many patients have premonitory symptoms suggestive of a viral illness, and an abrup onset is not unusual. Sinus tachycardia and low-grade fever are also common. The diagnosis of acute pericarditis is established when a patient has at least two of the following symptoms or signs: chest pain consistent with pericarditis, pericardial friction rub, typical ECG changes, or a pericardial effusion of more than trivial size. Because the rub and ECG findings may be transient, frequent auscultation and ECG recordings can be helpful in establishing the diagnosis.

Figure 1. Typical Electrocardiogram in a Patient with Acute Pericarditis.

What is the general approach when acute pericarditis is suspected or confirmed?

Appropriate tests include a complete blood count with a differential count, a high-sensitivity test of C-reactive protein, measurements of troponin I or T and serum creatinine, and liver-function tests. A chest radiograph should always be obtained, and findings should be normal unless there is a large pericardial effusion or an associated pulmonary disorder. An echocardiogram is routinely indicated for patients with suspected or confirmed pericarditis. The most important rationale is detection of a pericardial effusion, which can cause or threaten to cause cardiac tamponade without enlarging the cardiac silhouette on a chest radiograph.

Figure 2. Suggested Initial Approach for a Patient Presenting with Chest Pain Suggestive of Acute Pericarditis.

Morning Report Questions

Q: What is the treatment for acute pericarditis?

A: Nonsteroidal antiinflammatory drugs (NSAIDs) have long been the mainstay of the initial treatment of acute pericarditis. The most commonly used agents are ibuprofen (600 to 800 mg every 6 to 8 hours), indomethacin (25 to 50 mg every 8 hours), and aspirin (2 to 4g daily in divided doses). Patients receiving these drugs should also receive a proton pump inhibitor for gastric protection. On the basis of observational data from a relatively small number of patients with recurrent pericarditis, the European Society of Cardiology concluded in its 2004 guidelines that there was sufficient evidence to recommend colchicine combined with an NSAID for initial treatment of a first bout of pericarditis. More recently, evidence from the Investigation on Colchicine for Acute Pericarditis (ICAP) randomized clinical trial, involving patients with a first episode of pericarditis, strongly supported this recommendation. The optimal duration of treatment is uncertain. For colchicine, a 3-month course is reasonable on the basis of results from the ICAP trial. The usual duration of NSAID treatment, supported by expert opinion, is 1 to 2 weeks, with the actual duration driven by clinical response.

Q: What clinical course can be expected for most patients diagnosed with acute pericarditis?

A: In 70 to 90% of patients, acute idiopathic pericarditis is self-limited, responds promptly to initial treatment, and completely resolves. In a small number of patients, probably less than 5%, the condition does not respond satisfactorily to initial treatment, and in 10 to 30% of patients, recurrences develop after a satisfactory initial response. Most patients have only one or two recurrences, but a small fraction (probably less than 5% of the total population with acute pericarditis) have multiple recurrences with considerable disability. Ultimately, recurrences cease in the majority of cases.

Smoking Cessation

Posted by Carla Rothaus • December 19th, 2014

In a trial involving smokers who called the New Zealand national quitline, cytisine (a partial agonist of the nicotinic acetylcholine receptor) was superior to nicotine-replacement therapy in helping smokers quit. Nausea and sleep disorders were more frequent with cytisine.

Four systematic reviews report cytisine to be superior to placebo for short-term and long-term smoking abstinence. No trials have compared cytisine with nicotine-replacement therapy; a pragmatic, open-label, noninferiority trial conducted in New Zealand investigated whether cytisine was at least as effective as nicotine-replacement therapy.

Clinical Pearls

What is cytisine?

Cytisine is a plant-based alkaloid found in members of the Leguminosae family. Like varenicline, cytisine is a partial agonist of nicotinic acetylcholine receptors (nAChRs), with an affinity for the alpha4beta2 receptor subtype, and a half-life of 4.8 hours. Cytisine remains relatively unknown outside Eastern Europe despite calls for licensing worldwide because of its proven benefits, low cost as compared with other cessation medications (cytisine, $20 to $30 for 25 days; nicotine-replacement therapy, $112 to $685 for 8 to 10 weeks; varenicline, $474 to $501 for 12 weeks), and low cost per quality-adjusted-life-year.

Is cytisine as effective as nicotine-replacement therapy for smoking cessation?

Cytisine was not only noninferior to nicotine-replacement therapy but had superior effectiveness: 1-month continuous abstinence rates were significantly higher in the cytisine group (40%, 264 of 655) than in the nicotine-replacement therapy group (31%, 203 of 655) (risk difference, 9.3 percentage points; 95% confidence interval [CI], 4.2 to 14.5; number needed to treat, 11). The effectiveness of cytisine for continuous abstinence was superior to that of nicotine-replacement therapy at 1 week, 2 months, and 6 months.

Table 2. Continuous Abstinence and 7-Day Point-Prevalence Abstinence According to Treatment Group, According to the Intention-to-Treat Analysis.

Morning Report Questions

Q: Is cytisine equally effective in men and women?

A: Among secondary outcomes, prespecified analyses conducted according to sex showed a significantly higher 1-month continuous abstinence rate with cytisine in women and showed no significant difference (noninferiority) in men (P=0.011 for heterogeneity). The higher quit rate observed in women taking cytisine has not been previously reported in studies of nAChR partial agonists. This finding could be the result of chance (since data were not adjusted for multiplicity) but warrants further investigation, since several reviews of nicotine-replacement therapy have reported lower quit rates in women than in men, possibly as a result of biologic and psychosocial differences.

Q: How do the safety profiles of cytisine and nicotine-replacement therapy compare?

A: Self-reported adverse events occurred more frequently in the cytisine group (288 events reported by 204 participants) than in the nicotine-replacement-therapy group (174 events reported by 134 participants), with an incidence rate ratio of 1.7 (95% CI, 1.4 to 2.0; P<0.001). The majority of adverse events were nonserious and were mild to moderate in severity. The most frequent adverse events in the cytisine group were nausea and vomiting and sleep disorders.

Table 3. Summary of All-Cause Adverse Events.

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.