Letrozole or Clomiphene for Infertility in PCOS

Posted by Sara Fazio • July 11th, 2014

This double-blind, multicenter, randomized trial showed that letrozole, as compared with clomiphene, was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome.

The PCOS, which is diagnosed on the basis of hyperandrogenism, oligo-ovulation with associated oligomenorrhea, and polycystic ovaries on ultrasonography, affects 5 to 10% of reproductive-age women and is the most common cause of anovulatory infertility.

Clinical Pearls

What are the potential drawbacks to the use of clomiphene citrate for ovulation induction?

Clomiphene citrate, a selective estrogen-receptor modulator that antagonizes the negative feedback of estrogen at the hypothalamus with a consequent increase in ovarian stimulation by endogenous gonadotropin, has been used for this indication for decades.  Clomiphene has drawbacks, including its overall poor efficacy (only a 22% rate of live birth with up to six cycles of clomiphene in our previous study), a relatively high multiple-pregnancy rate (3 to 8%) as compared with the rate associated with unassisted conception   (<1%), and an undesirable side-effect profile, including mood changes and hot flashes.

What was the primary outcome of this study comparing clomiphene to letrozole for ovulation induction in infertile women with the polycystic ovary syndrome?

The group of women who received letrozole had more cumulative live births than the group of women who received clomiphene (103 of 374 women [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth with letrozole, 1.44; 95% confidence interval, 1.10 to 1.87).   There were no significant between-group differences in live-birth rates according to treatment cycle. The live-birth rates after an anovulatory cycle were similar with and without progestin-induced withdrawal bleeding in both treatment groups.

Table 2. Outcomes with Regard to Live Birth, Ovulation, Pregnancy, Pregnancy Loss, and Fecundity.

Figure 1. Kaplan-Meier Curves for Live Birth.

Morning Report Questions

Q: What were secondary study outcomes?

A: The rates of pregnancy loss after conception were similar in the two treatment groups. The ovulation rate was significantly higher with letrozole than with clomiphene at each monthly visit (P<0.01 for all comparisons) beginning with the second visit. Among patients who ovulated, there was a significantly greater chance of singleton pregnancy with letrozole than with clomiphene (P=0.03). The sex ratio at birth favored girls.

Table 2. Outcomes with Regard to Live Birth, Ovulation, Pregnancy, Pregnancy Loss, and Fecundity. 

Q: How did adverse events compare between the two treatment groups?

A: Three serious adverse events related to ovarian-cyst formation occurred during infertility treatment: two with letrozole (a ruptured corpus luteum cyst in one patient and hospitalization for the drainage and removal of an ovarian cyst in another patient) and one with clomiphene (ovarian torsion). Clomiphene was associated with a significantly higher incidence of hot flushes; letrozole was associated with significantly higher incidences of fatigue and dizziness. During pregnancy, the most common complication was gestational diabetes, followed by preeclampsia or eclampsia, preterm labor, and premature rupture of membranes, with no significant differences between treatment groups. There were five major congenital anomalies (four with letrozole and one with clomiphene); the between-group difference was not significant (P=0.65).

Table 3. All Serious Adverse Events, plus Other Adverse Events with Significant Differences between the Treatment Groups.

CNS Fungal Infections

Posted by Sara Fazio • July 11th, 2014

Molds are ubiquitous in soil, water, and decaying vegetation and can cause devastating infections that are difficult to treat. This review summarizes the epidemiologic profiles, clinical characteristics, and treatment of mold infections of the central nervous system.

Molds are ubiquitous organisms found in soil, water, and decaying vegetation. All have septate, angular, branching hyphae in tissue, with the exception of those in the order Mucorales, which have broad, ribbonlike, nonseptate or hyposeptate hyphae.

Clinical Pearls

What is the typical mechanism by which fungal infections reach the CNS?

The respiratory tract is usually the portal of entry, with subsequent hematogenous dissemination to the CNS. However, direct inoculation of CNS or paraspinal tissue as a result of surgery, trauma, intravenous drug use, or contaminated medical supplies may also occur in immunocompetent persons. Organisms may also spread to the CNS from adjacent structures, including the sinuses, mastoid, and orbit. Infection of the ethmoid sinuses may lead to cavernous sinus thrombosis as a result of invasion of the emissary veins that drain the sinuses. Hyphae can invade from the ethmoid sinuses through the lamina papyracea and into the periorbital space, thus threatening the eye, extraocular muscles, and posterior apical structures, including the optic nerve. Angioinvasion is common in immunocompromised patients and accounts for the hematogenous dissemination from the lungs that causes focal neurologic deficits.

What are the characteristics of CNS aspergillosis?

The risk factors for CNS aspergillosis include neutropenia, systemic glucocorticoid treatment, mastoidectomy, spinal anesthesia, and paraspinal glucocorticoid injections. Focal neurologic deficits and seizures caused by stroke or mass effect are the most common clinical manifestations of CNS aspergillosis. Meningeal signs are uncommon, and their presence is indicative of a subarachnoid hemorrhage. CNS aspergillosis should be high on the list of disorders in the differential diagnosis for patients with immunosuppression and focal brain lesions, especially those with characteristic pulmonary infiltrates in whom focal neurologic deficits or focal seizures develop. Recovery of aspergillus from pulmonary lesions with the use of bronchoalveolar lavage or fine-needle aspiration should be pursued when possible. An enzyme immunoassay for detection of galactomannan in serum or bronchoalveolar lavage fluid should be performed when feasible. Galactomannan and 1,3-(beta)-d-glucan may be found in the serum or CSF of patients with CNS aspergillosis. Voriconazole is the first-line treatment for CNS aspergillosis.

Morning Report Questions

Q: What are typical features of cerebral mucormycosis?

A: Cerebral mucormycosis, which is perhaps the most aggressive mold infection of the CNS, constitutes a medical emergency. Diabetes mellitus and iron-overload conditions are distinctive risk factors for the development of mucormycosis. In patients with neutropenia or patients receiving glucocorticoid therapy, mold infections of the CNS develop as sino-orbital infections or through hematogenous dissemination of pulmonary mucormycosis. In contrast, patients with diabetes mellitus usually present with sino-orbital mucormycosis and seldom present with pulmonary or disseminated infection. Among intravenous drug users, CNS mucormycosis is a relatively common cause of intracerebral fungal abscesses. Perhaps more than any other infection, mucormycosis of the ethmoid sinuses may involve all structures along its invasive path, including the orbit and eye, bone, and brain tissue. Because venous drainage of the ethmoid sinuses extends into the cavernous sinuses, ethmoidal mucormycosis carries a high risk of cavernous sinus thrombosis. Successful management of rhinocerebral mucormycosis depends not only on early diagnosis but also on primary antifungal therapy with amphotericin B, reversal of host impairments and timely surgical intervention, when indicated.

Q: What are the features of CNS infection with fusarium species?

A: CNS fusariosis develops predominantly in patients with prolonged neutropenia. These organisms are highly angioinvasive and cause hemorrhagic infarction with strokelike events. Portals of entry include the lungs, sinuses, vascular catheters, and distinctively, periungual lesions (paronychia in patients with neutropenia). Fusarium species are also most frequently associated with fungemia, multiple erythematous nodular cutaneous lesions, and septic arthritis. A definitive mycologic diagnosis can be rapidly established by biopsy and culture of cutaneous lesions. As compared with other mold infections of the CNS, disseminated fusariosis is more commonly associated with bilateral endophthalmitis, which may lead to blindness. Fusarium species vary in their susceptibility to antifungal agents. Voriconazole is licensed for second-line therapy; however, amphotericin B also has been used successfully.

Take the Case Challenge

Posted by Jennifer Zeis • July 10th, 2014

A 41-year-old man was admitted to the hospital in midsummer because of fever, rash, pancytopenia, and abnormal results of liver-function tests. What is the diagnosis? What diagnostic tests are indicated?

Read the case description for the next Case Record of the Massachusetts General Hospital, and then vote and comment now on NEJM.org. In a few days, find the answer in the full text of the Case Record to be published July 24.

Follow the conversation with #NEJMCases on Twitter or Facebook.

Dupilumab as a Treatment for Atopic Dermatitis

Posted by Rachel Wolfson • July 9th, 2014

For thousands of years, our knowledge of medications has largely been based on trial and error: we haphazardly used substances and learned from the effects. Within the last half a century, however, rational drug design slowly took to the forefront as scientific discoveries improved our understanding of the underlying pathogenesis of diseases. While there have not been many victories for rational drug design so far, dupilumab is a key one on a small but growing list. As a monoclonal antibody that targets cytokines involved in type 2 helper T cell (Th2) activation, dupilumab has already demonstrated preliminary efficacy for asthma, a disease which is known to be driven, at least in part, by Th2 activation. Furthermore, Th2 activation has also been implicated in the pathogenesis of atopic dermatitis, a disease characterized by skin barrier abnormalities, Th2 immune responses, and pruritis.

To evaluate the importance of Th2 activation in the pathogenesis of atopic dermatitis and the efficacy of dupilumab as a treatment, Beck and colleagues conducted four randomized, double-blinded, placebo-controlled clinical trials and reported their results in this week’s NEJM. Two of the trials (studies M4A and M4B) were originally designed primarily for safety analysis but the clinical effects were striking. The patients were randomly assigned to four weeks of treatment with either dupilumab or placebo. Another trial (study M12) followed 109 patients for 12 weeks after initiating monotherapy with either dupilumab or placebo. The primary objective was to assess clinical efficacy. Finally, a fourth trial (study C4) compared dupilumab in combination with topical glucocorticosteroids to placebo with topical glucocorticosteroids. The primary endpoints after four weeks of combination therapy were the incidence and severity of adverse events.

In studies M4A and M4B, patients treated with dupilumab showed rapid and dose dependent improvements in all clinical outcomes that were tested, such as pruritis scale rating and improvement in eczema area. This improvement was also seen in patients treated with dupilumab at the four-week point in study M12, and this treatment group continued to improve throughout the entire 12-week course. Similarly, in study C4, patients treated with dupilumab in combination with topical glucocorticosteroids had better improvements in clinical outcomes than those treated with placebo and topical glucocorticosteroids. Finally, in terms of safety measures, there were more mild to moderate adverse events in the patients treated with dupilumab (i.e. nasopharyngitis and headache), but there were more serious adverse events in the placebo group, mostly due to skin infections and atopic dermatitis.

Overall, the data provide solid evidence for the key role of Th2 activation in the pathogenesis of the disease; these trials cannot address the clinical utility of the treatment. This advance reflects the importance of studying the molecular underpinning of diseases, because if we can truly understand the biology, we will find effective therapies for even the most stubborn illnesses.

Acute Kidney Injury and Chronic Kidney Disease

Posted by Sara Fazio • July 4th, 2014

This new review article considers evidence that acute and chronic kidney diseases are not distinct entities but rather are closely interconnected.  The implications of this insight are discussed in terms of the approach to patients with kidney disease.

During the past decade, separate conceptual models for chronic kidney disease and acute kidney injury were developed to facilitate organized approaches to clinical research and trials. Recent epidemiologic and mechanistic studies suggest that the two syndromes are not distinct entities but rather are closely interconnected — chronic kidney disease is a risk factor for acute kidney injury, acute kidney injury is a risk factor for the development of chronic kidney disease, and both acute kidney injury and chronic kidney disease are risk factors for cardiovascular disease.

Clinical Pearls

What is considered to be the most important risk factor for acute kidney injury?

Multiple risk factors for acute kidney injury are now known to include advanced age, diabetes mellitus, and black race. Similar risk factors have been identified for chronic kidney disease. However, the most important risk factor for acute kidney injury is preexisting chronic kidney disease, which increases risk by as much as 10 times, as compared with the absence of chronic kidney disease.

Figure 1. Acute Kidney Injury and Chronic Kidney Disease as an Interconnected Syndrome.

How does acute kidney injury impact the risk of developing chronic kidney disease?

Several findings suggest that acute kidney injury not only is directly linked to the progression of chronic kidney disease but causes chronic kidney disease as well. First, the increased severity of acute kidney injury is associated with the development of chronic kidney disease. Second, multiple episodes of acute kidney injury predict the development of chronic kidney disease.

Morning Report Questions

Q: What is the association between acute kidney injury or chronic kidney disease and cardiovascular disease?

A: In addition to being associated with chronic kidney disease, acute kidney injury is linked to the development and treatment of cardiovascular disease. A strong association between chronic kidney disease and an increased risk of cardiovascular events is well documented. Patients who survive an episode of acute kidney injury are also at risk for major adverse cardiovascular events, as well as for progression to chronic kidney disease, regardless of whether there is underlying cardiovascular disease. Patients with acute kidney injury after coronary angiography are at risk for hospitalization for cardiovascular causes, myocardial infarction, and vessel reocclusion; the severity of acute kidney injury has been associated with hospitalization for heart failure. Acute kidney injury is associated with higher rates of death or subsequent hospitalization for stroke, heart failure, or myocardial infarction than the rates associated with previous myocardial infarction.

Figure 1. Acute Kidney Injury and Chronic Kidney Disease as an Interconnected Syndrome.

Q: What are strategies for management after an episode of acute kidney injury?

A: Patients with acute kidney injury should have periodic assessment of renal function and the urinary albumin-to-creatinine ratio to assess prognosis and outcome after discharge. The appropriate treatment for patients who survive an episode of acute kidney injury, regardless of whether they have chronic kidney disease, is unclear. Reasonable therapeutic approaches to patients who do not have preexisting kidney disease but do have evidence of renal injury include, first, “do no harm,” by avoiding nephrotoxic medications, including nonsteroidal antiinflammatory drugs and radiocontrast agents. In addition, one needs to determine the appropriate treatment for important risk factors for chronic kidney disease such as diabetes and hypertension. The preventive use of inhibitors of the renin-angiotensin-aldosterone system, low-sodium diets, or both should be evaluated in such patients. The authors note that it is not known whether these therapeutic approaches ameliorate or worsen outcomes in patients with acute kidney injury or in those with combinations of acute kidney injury and chronic kidney disease. Patients who have had acute-on-chronic episodes of acute kidney injury and chronic kidney disease should be followed by primary care physicians as well as nephrologists to ensure the highest standards of care.

Giant-Cell Arteritis and Polymyalgia Rheumatica

Posted by Sara Fazio • July 4th, 2014

Both giant-cell arteritis and polymyalgia rheumatica are immune-mediated diseases that are treated with glucocorticoids, with higher doses used for giant-cell arteritis. In our latest Clinical Practice article, prompt initiation of high doses and a biopsy are recommended when ischemic optic neuropathy is suspected.

Giant-cell arteritis is an inflammatory vasculopathy that typically occurs in medium and large arteries with well-developed wall layers and adventitial vasa vasorum. The vascular beds that are usually affected include the external carotid branches (e.g., temporal and occipital arteries), the ophthalmic, vertebral, distal subclavian, and axillary arteries, and the thoracic aorta. Polymyalgia rheumatica causes aching and stiffness in selected muscle groups, predominantly in the neck, shoulders, upper arms, and pelvic girdle. Symptoms are most pronounced in the morning.

Clinical Pearls

What is the epidemiology of giant-cell arteritis and polymyalgia rheumatica, and how often do the diagnoses overlap?

Giant-cell arteritis and polymyalgia rheumatica have multiple risk factors and pathogenic abnormalities in common. Approximately 50% of patients with giant-cell arteritis present with polymyalgia rheumatica before, at the time of, or after the diagnosis of vasculitis. Symptoms of polymyalgia rheumatica often appear when the therapy for giant-cell arteritis is being tapered. Both giant-cell arteritis and polymyalgia rheumatica are diseases that affect the elderly, with a peak incidence at the age of 70 to 80 years; age (50 years or older) is considered a criterion for the diagnosis. Women account for 65 to 75% of patients. Polymyalgia rheumatica occurs at a frequency that is 3 to 10 times that of giant-cell arteritis.

What are laboratory results in patients with giant-cell arteritis and polymyalgia rheumatica?

Marked elevations in the erythrocyte sedimentation rate (ESR) and the level of C-reactive protein (CRP) are common in giant-cell arteritis and polymyalgia rheumatica, as are the presence of thrombocytosis and anemia. In a cohort of 764 patients with suspected giant-cell arteritis who underwent biopsy, with the diagnosis confirmed in 177 patients, the sensitivity of an elevated ESR was 84% and that of an elevated CRP level was 86%; the specificity of these markers was low, however, at 30%. Only 4% of patients with confirmed giant-cell arteritis had both a normal ESR and a normal CRP level at the time of diagnosis. Assessment of inflammatory markers is helpful during diagnostic evaluation and long-term monitoring, but elevated levels of these markers should not be the only indication for immunosuppressive therapy. No highly specific biomarkers for giant-cell arteritis and polymyalgia rheumatica have been validated.

Morning Report Questions

Q: What is the standard for diagnosis of suspected giant-cell arteritis?

A: In cases of suspected giant-cell arteritis, histologic verification of vasculitis should be sought by means of a temporal-artery biopsy with assessment of a vascular segment that is 1.5 to 2.0 cm in length. Histologic analysis is the standard for diagnosis; it can detect small inflammatory infiltrates and can also distinguish giant-cell arteritis from non-giant-cell arteritis arteritides (e.g., ANCA-associated vasculitis). High-field-strength MRI may emerge as a method that is sensitive to the detection of temporal-artery inflammation, but neither ultrasonography nor MRI has yet replaced temporal-artery biopsy, which is highly sensitive for even minor inflammatory changes.

Q: What is the optimal treatment for giant-cell arteritis and polymyalgia rheumatica?

A: Giant-cell arteritis and polymyalgia rheumatica are responsive to glucocorticoids. Most treatment recommendations are based on clinical experience rather than the results of randomized, controlled trials. Therapy for giant-cell arteritis is initiated with prednisone at a dose of 1 mg per kilogram of body weight per day. Given the risk of irreversible ischemic complications, new-onset clinical manifestations of disease indicating an unstable supply of blood to the eyes or the central nervous system (e.g., arteritic optic neuropathy) are typically managed with intravenous pulse therapy (e.g., 1000 mg of methylprednisolone per day for 3 consecutive days) to optimize immunosuppression and suppress tissue edema. The doses of glucocorticoids used to treat polymyalgia rheumatica are much lower than those used for the treatment of giant-cell arteritis. In the majority of patients, a dose of 15 to 20 mg of prednisone per day is sufficient to control myalgia. No glucocorticoid-sparing agents have been approved for the treatment of giant-cell arteritis or polymyalgia rheumatica.

Glucocorticoid Injections for Spinal Stenosis

Posted by Daniela Lamas • July 2nd, 2014

Spinal stenosis is a pain – both for those who suffer it, and the doctors who treat it.

As surgery is a potentially risky option with uncertain benefit, many doctors turn to glucocorticoid injections for their patients, to decrease pain and increase mobility.  An estimated ten to eleven million such injections are performed in the US annually, numbers that have grown rapidly in recent years.

But do glucocorticoid injections actually help? A recent review from the North American Spine Society highlighted the paucity of data, concluding that there is insufficient evidence to make a recommendation either for or against. And this therapy isn’t always benign. While serious complications are rare, complications including paralysis and nerve damage have been reported.

With this background, Janna Friedly and colleagues set out to determine whether glucocorticoid injections actually benefit patients with spinal stenosis. Their results, published in this week’s issue of NEJM, suggest that the increasingly popular treatment is no better than their comparator, an injection of lidocaine alone.

The study investigators enrolled 400 patients with lumbar spinal stenosis, whose disease caused them moderate-to-severe leg pain and disability and who had been referred for steroid injections. All study participants were older than 50 and hadn’t ever undergone lumbar surgery, or received epidural steroid injections in the previous six months. Patients were randomly assigned to either epidural glucocorticoid injection with lidocaine, or lidocaine injection alone. The participants could receive a second injection three weeks later, at the patient’s discretion.

After six weeks, patients in both groups were asked to rate their average buttock, hip and leg pain in the previous week and to fill out a questionnaire that quantifies degree of pain and associated disability. They were also asked to respond to surveys of depression, anxiety and quality of life.

The results? Both groups of patients reported improvement in their pain and physical function at three and six weeks, whether or not their injections included glucocorticoids. At six weeks, there were no significant differences in pain or function ratings between the two groups. Of note, the patients randomly assigned to the glucocorticoid injections were more likely to have improvement in depressive symptoms. Those receiving glucocorticoid injections had a higher rate of adverse events, although the complications were generally mild.

In an accompanying editorial discussing these results, orthopedic surgeon Gunnar Anderson notes the difficulties inherent in trials of treatments for spinal stenosis. For one, spinal stenosis is a heterogeneous disease both in terms of cause – congenital versus degenerative – location, and extent. Additionally, Friedly’s trial did not include a control group that received sham injections, leaving open the question of whether the benefit seen in both groups could be due to the lidocaine injection itself, although this would be unlikely.

Despite these questions, Anderson concludes that the study “raises serious questions about benefits from epidural corticosteroid injections for spinal stenosis…Patients should be informed that currently best available data have not supported a significant long term clinical benefit overall, and that complications are possible.”

Dying with Dignity in the Intensive Care Unit

Posted by Sara Fazio • June 27th, 2014

It is common for patients to have an expected death in an ICU. The final review in the Critical Care series covers issues related to the end of life in the absence of discordance between the patient’s family and caregivers.

The traditional goals of intensive care are to reduce the morbidity and mortality associated with critical illness, maintain organ function, and restore health. Despite technological advances, death in the intensive care unit (ICU) remains commonplace.

Clinical Pearls

According to the authors, what are the principles of “dying with dignity?”

The definition of “dying with dignity” recognizes the intrinsic,unconditional quality of human worth but also external qualities of physical comfort, autonomy, meaningfulness, preparedness, and interpersonal connection. Respect should be fostered by being mindful of the “ABCDs” of dignity-conserving care (attitudes, behaviors, compassion, and dialogue).

Table 1. Examples of the ABCDs of Dignity-Conserving Care.

How is palliative care defined by the World Health Organization?

The World Health Organization defines palliative care as “an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual.” Palliative care, which is essential regardless of whether a medical condition is acute or chronic and whether it is in an early or late stage, can also extend beyond the patient’s death to bereaved family members.

Figure 1. Curative and Palliative Approaches to Care throughout a Critical Illness.

Morning Report Questions

Q: How is family satisfaction in the ICU setting impacted by communication with clinicians?

A: Clear, candid communication is a determinant of family satisfaction with end-of-life care. Notably, measures of family satisfaction with respect to communication are higher among family members of patients who die in the ICU than among those of ICU patients who survive, perhaps reflecting the intensity of communication and the accompanying respect and compassion shown by clinicians for the families of dying patients. The power of effective communication also includes the power of silence. Family satisfaction with meetings about end-of-life care in the ICU is greater when physicians talk less and listen more.

Q: How many physicians in the ICU feel comfortable making recommendations to forgo the use of life-supporting technology, and how many report consistently doing so?

A: Physicians in the ICU sometimes make recommendations to forgo the use of life-support technology. In one study involving surrogates of 169 critically ill patients, 56% preferred to receive a physician’s recommendation on the use of life support, 42% preferred not to receive such a recommendation, and 2% stated that either approach was acceptable. A recent survey of ICU physicians showed that although more than 90% were comfortable making such recommendations and viewed them as appropriate, only 20% reported always providing recommendations to surrogates, and 10% reported rarely or never doing so. In this study, delivering such recommendations was associated with perceptions about the surrogate’s desire for, and agreement with, the physician’s recommendations. Other potential influences are uncertainty, personal values, and litigation concerns.

Prophylaxis against Venous Thromboembolism in Ambulatory Cancer Patients

Posted by Sara Fazio • June 27th, 2014

Patients with cancer are at increased risk for thrombosis, and those with thrombi have poorer overall survival rates than those without. In a new review article, Dr. Jean Connors from Brigham and Women’s Hospital and Dana Farber Cancer Institute summarizes available data and provides guidance for determining which patients might benefit from thromboprophylaxis.

The incidence of cancer-associated thrombosis is increasing, probably because of a combination of improved treatment outcomes resulting in longer patient survival, more aggressive and prothrombotic treatment regimens, an aging population, and increased detection owing to improvements in imaging technology and the frequency of imaging.

Clinical Pearls

What is the differential risk of venous thromboembolism among patients with cancer compared to patients without cancer?

The risk of venous thromboembolism is four to seven times as high among patients with cancer as among persons without this disease.  This risk is highest among patients with certain types of solid tumors and hematologic cancers and is increased among patients who are receiving chemotherapy or radiotherapy, who are undergoing operative procedures, who have metastatic disease, or who have inherited thrombophilias.

What are results in two recent trials of low-molecular-weight heparin preparations used for prophylaxis in cancer patients?

The PROTECHT [Prophylaxis of Thromboembolism during Chemotherapy] study randomly assigned 1150 ambulatory patients with cancer to receive prophylactic nadroparin or placebo. The nadroparin group, as compared with the placebo group, had a 50% reduction in composite venous and arterial events (2.0% vs. 3.9%, P=0.02). The SAVE-ONCO trial randomly assigned 3212 ambulatory patients receiving chemotherapy for locally advanced solid tumors or metastatic cancer to receive a prophylactic dose of semuloparin or placebo. The overall incidence of venous thromboembolism was 1.2% in the semuloparin group, as compared with 3.4% in the placebo group (hazard ratio, 0.36; 95% confidence interval, 0.21 to 0.60; P<0.001).

Morning Report Questions

Q: At what platelet threshold should anticoagulant therapy be held in patients with cancer receiving chemotherapy and prophylactic anticoagulation?

A: Ambulatory patients with cancer who are receiving chemotherapy and prophylaxis against venous thromboembolism can be more closely monitored, and anticoagulation therapy can be withheld if there are changes in renal function or the platelet count that suggest an increased risk of bleeding. All guidelines suggest withholding any dose of anticoagulation drug if the platelet count is less than 50,000 per cubic millimeter; however, for very high-risk patients, the continued use of prophylactic anticoagulation therapy can be considered if the platelet count is more than 30,000 per cubic millimeter.

Q: What are current guidelines on the use of prophylactic anticoagulation against venous thromboembolism in ambulatory patients with cancer?

A: Current guidelines from the American College of Chest Physicians (ACCP), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN) have subtle differences, but all advise against the use of routine prophylaxis against venous thromboembolism in most ambulatory patients with cancer. An exception is made for patients with multiple myeloma who have received either multiagent chemotherapy or thalidomide-lenalidomide regimens that include dexamethasone; among these patients, rates of venous thromboembolism of 23 to 75% have been reported.

Table 2. Comparison of Recommendations Regarding Prophylaxis against Venous Thromboembolism.

Atrial Fibrillation in Cryptogenic Stroke

Posted by Carla Rothaus • June 25th, 2014

Your 69-year-old patient has just had an ischemic stroke. Fortunately, he should make a good recovery. And yet, you feel unsettled. A standard post-stroke work up – 12-lead ECG, ambulatory 24-hour Holter ECG monitoring, brain and neurovascular imaging, and echocardiography – failed to reveal a cause for his stroke, putting it in the “cryptogenic” stroke category. You worry though, that he might have intermittent episodes of atrial fibrillation you simply have been unable to detect….

Patients who have had a stroke or transient ischemic attack (TIA) caused by atrial fibrillation are at significant risk for recurrent stroke, yet atrial fibrillation is often asymptomatic and intermittent (paroxysmal), and may escape detection with short periods of ECG monitoring. Distinguishing strokes caused by atrial fibrillation from those without identifiable cause has important therapeutic implications. While anti-platelet therapy is the recommended treatment for cryptogenic stroke, it is much less effective than anticoagulation in preventing recurrent stroke when the cause is atrial fibrillation. Multiple observational studies have suggested that prolonged ECG monitoring is superior to conventional 24-hour ECG monitoring in identifying atrial fibrillation in patients with stroke. Data from randomized clinical trials have been lacking however, and new practice guidelines have not been adopted.

This week’s NEJM includes the results of two studies designed to address this void. Gladstone et al. conducted a multicenter trial (EMBRACE) that randomized 572 patients to undergo ambulatory monitoring with either a 30-day event-triggered external loop recorder or one additional round of 24-hour Holter monitoring. Eligible patients were 55 years or older, had no history of atrial fibrillation, and had been given a diagnosis of cryptogenic stroke or TIA after standard work up was negative. The primary outcome was detection of one or more episodes of ECG-documented atrial fibrillation or flutter lasting 30 seconds or longer within 90 days after randomization. A multicenter randomized controlled trial performed by Sanna et al. (CRYSTAL AF) compared prolonged monitoring with an implantable loop recorder to conventional ECG monitoring in 441 patients 40 years or older with recent cryptogenic stroke or TIA.

Both studies showed that long-term monitoring in the intervention group resulted in a higher rate of detection of atrial fibrillation. In EMBRACE, atrial fibrillation was detected in about 1 out of 6 patients in the intervention group, as compared to about 1 out of 30 in the control group; the difference was significant at the P<0.001 level. In CRYSTAL AF, the rate of detection of atrial fibrillation was about 1 out of 11 among patients in the intervention group, as compared to less than 1 in 50 among patients in the control group; this difference was also significant (P<0.001).

In an accompanying editorial, Dr. Hooman Kamel (Weill Cornell Medical College) calls the study findings an “important advance,” and concludes that “prolonged monitoring of heart rhythm should now become part of the standard care of patients with cryptogenic stroke.” He notes however that prior studies establishing the benefit of antithrombotic therapy for paroxysmal atrial fibrillation included patients whose arrhythmia was detected with conventional monitoring; additional research is needed, he cautions, to assure that brief episodes of paroxysmal atrial fibrillation detected with prolonged monitoring present a similar stroke risk and merit similar treatment.

NEJM Executive Editor Dr. Gregory Curfman adds, “These studies support the application of prolonged ECG monitoring for the detection of paroxysmal atrial fibrillation in patients with stroke. This approach may allow more targeted use of anticoagulation for stroke prevention.”