Comfort Care

Posted by Carla Rothaus • December 26th, 2015

Moritz Electrolyte ChallengeThe symptoms that cause suffering in hospitalized patients who are near death can be addressed by a variety of palliative interventions that improve the patient’s remaining life and ease the stress on both the patient and family members. A new review article summarizes. 

Palliative care services can reduce the distress caused by symptoms and improve the quality of life of patients near the end of life. However, the current scarcity of board-certified palliative care specialists — a workforce shortage that is projected to continue far into the future — means that the responsibility for ensuring excellent end-of-life care for dying patients will continue to fall primarily on generalists and on specialists in areas other than palliative care. Thus, familiarity with basic comfort measures is an essential skill for all clinicians who are caring for patients whose death is imminent.

Clinical Pearls

• What is meant by “comfort care”?

Comfort care requires the meticulous palliation of troubling symptoms and offering of skilled psychosocial and spiritual support to the patient and the patient’s family. However, the term is often used in a misleading or imprecise manner — for example, when such care is automatically considered equivalent to a do-not-resuscitate order and, perhaps even without discussion with the patient, is extrapolated to mean the exclusion of a full range of palliative measures appropriate for a dying patient. Rather than simply writing orders for “comfort care” (or “intensive comfort measures,” the term that the authors prefer), the medical team should review the entire plan of care and enter explicit orders to promote comfort and prevent unnecessary interventions.

Table 1. Guidelines for Physicians in Discussing Values, Goals, and Preferences with Patients Near the End of Life.

Table 2. Guidelines for Physicians Providing Comfort Care for Hospitalized Patients Who Are Near the End of Life.

• What is the treatment of choice for dyspnea in patients approaching death?

Dyspnea can be a debilitating symptom and may lead to substantial anxiety in the patient about the possibility of suffocating. A search for the underlying cause, especially when the degree of dyspnea changes rapidly, may occasionally be appropriate. However, such investigations should not be allowed to delay the treatment of symptoms. Opioids, given either orally or intravenously, are the treatment of choice for dyspnea and have been studied thoroughly in patients with COPD and patients with cancer; they have been found to be effective in alleviating dyspnea and, when used carefully, not to have serious side effects, such as respiratory depression. Patients are regularly given supplemental oxygen for dyspnea, but systematic reviews have found no benefit for patients with cancer or heart failure who do not have hypoxemia; however, oxygen may provide some relief for patients with COPD who do not have hypoxemia.

Morning Report Questions

Q: In the dying patient, does the treatment of neuropathic pain differ from that for somatic or visceral pain?

A: Neuropathic pain should be distinguished from somatic or visceral pain, since opioids alone may not provide adequate analgesia for patients with neuropathic pain. For patients with only a few days to live, adjuvant analgesics used for neuropathic pain may not have time to take effect; however, glucocorticoids may be of benefit in treating acute neuropathic pain. The combination of morphine with gabapentin produces analgesia that is more effective than that provided by either agent alone. Other agents (such as transdermal lidocaine, antidepressants, and anticonvulsants) may be considered when longer survival is anticipated.

Table 3. Guidelines for the Management of Acute Pain at the End of Life.

Q: How should clinicians manage the excessive oral and pharyngeal secretions that are typically observed in the final days of life?

A: The inability to clear oral and tracheobronchial secretions is typically observed in the final days of life and can lead to gurgling sounds in the throat, sometimes referred to as a “death rattle.” Although family members and staff are often distressed by these sounds, they are unlikely to be disturbing to the dying patient, since they typically occur when the patient is unresponsive and lacks an effective cough reflex. The production of “grunting” sounds by the vocal cords is also common in dying patients. Simply repositioning the head may reduce these sounds and reassure loved ones that the patient is not in distress. No convincing evidence beyond clinical reports supports the commonly recommended use of antimuscarinic agents (e.g., atropine and glycopyrrolate) in patients with noisy breathing due to terminal respiratory secretions. A trial of glycopyrrolate can be considered, but the authors do not recommend its routine use, especially given the risk of such side effects as xerostomia, delirium, and sedation. Rather, clinicians should reassure and counsel family members and staff about the unlikelihood that the patient is experiencing discomfort from excessive secretions and about the lack of benefit and potential harm of treatment.

Table 5. Management of Symptoms Other Than Pain at the End of Life.

Selexipag for Pulmonary Hypertension

Posted by Carla Rothaus • December 26th, 2015

Selexipag for the Treatment of Pulmonary Arterial HypertensionAmong over 1100 patients with pulmonary arterial hypertension who received selexipag, an oral selective IP prostacyclin-receptor agonist, or placebo, the risk of the composite end point of death or complication was lower with selexipag than with placebo at 1.3 years of follow-up. A new Original Article summarizes.

Pulmonary arterial hypertension is a severe disease with a poor prognosis despite available treatment options. Current recommendations support the use of a combination of therapies that target the endothelin, nitric-oxide, and prostacyclin pathways. Sitbon et al. conducted a phase 3 trial to investigate the safety and efficacy of selexipag in patients with pulmonary arterial hypertension.

Clinical Pearls

• What is selexipag?

Selexipag is an oral selective IP prostacyclin-receptor agonist that is structurally distinct from prostacyclin. The agent targets the prostacyclin receptor, which is also called the IP receptor. There are 5 types of prostanoid receptors, and selexipag selectively targets the prostacyclin receptor, resulting in vasodilation and inhibition of vascular smooth muscle cell proliferation.

• Does selexipag reduce the risk of death or complications among patients with pulmonary arterial hypertension as compared to placebo?

In the event-driven study by Sitbon et al. involving patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower among patients who received selexipag than among those who received placebo. There was no significant difference in mortality between the two study groups. The effect of selexipag was consistent in all prespecified patient subgroups, including those defined according to the cause of the pulmonary arterial hypertension, disease severity, and baseline treatment. The addition of selexipag to a baseline regimen of two medications for pulmonary arterial hypertension resulted in benefits that were consistent with the overall treatment effect.

Figure 2. Primary Composite End Point.

Table 2. End Points Related to Pulmonary Arterial Hypertension and Death.

Morning Report Questions

Q: What adverse events are associated with selexipag?

A: In the study by Sitbon et al., the adverse events observed with selexipag were consistent with those typically observed with prostacyclin therapies. Headache, diarrhea, and nausea led to discontinuation of the study regimen more frequently in the selexipag group than in the placebo group. Overall, these adverse events were typically mild to moderate in severity and resulted in discontinuation in only a minority of cases. No serious adverse events were reported more frequently (i.e., at a rate >1% higher) in the selexipag group than in the placebo group.

Table 3. Most Frequent Adverse Events and Abnormal Laboratory Results.

Q: How is the dose of selexipag determined for each patient?

A: It has been postulated that the density of prostacyclin receptors varies substantially among patients and may influence the individualized dose required for each patient. In the Sitbon study, selexipag showed similar efficacy among patients who received a low-dose, medium-dose, and high-dose selexipag regimen. These data support the dose adjustment of selexipag to the highest dose at which the patient has manageable side effects and reflect the approach to dosing used with other therapies that target the prostacyclin pathway. This approach precluded the study authors from evaluating whether a fixed dose of selexipag would be equally effective in all patients.

The Outsiders

Posted by Ken Bernard • December 23rd, 2015

A few weeks ago we had our first Thanksgiving in our new home, complete with turkey costumes for the dogs and my wife’s best green bean casserole to date. We really feel like roots are starting to take. What was I most thankful for this holiday season? A home, a family, and the opportunity to bring happiness into our small part of the world. Or as my kookum would have said, “Someone to love, something to do, and something to wish for.”

Flagstaff is the tenth new city I’ve adopted, having moved frequently across the Midwest growing up, followed by New Haven for college and Boston for medical training. My parents separated when I was about three years old. I don’t remember much from that that time, except for the crying, the noise, and the movement. As I talk with my parents now, they tell a story which should be familiar to divorcees. They met young, loved fast, grew apart, and happiness together was unsustainable. As a result, I moved a lot, and events were, again, predictable and familiar to kids of divorcees. I showed up at a new school, often mid-year, got bullied, beat up, tried to fit in. When that failed, I retreated into school work, television, and sport. I found myself never feeling settled, always looking for acceptance, and never really at home. I grew up an outsider.

I write this not to be depressing or garner sympathy. My folks made the right call for our family. And despite the emotional toll, I always felt loved. They did the best they could and I love my parents. I took away a lot of really important lessons from that time. I add those hardships to the list of experiences I am thankful for, as they have allowed me to know why I am happy today. For example, I moved to three different reservations during those tumultuous years. I thought things would be easier than moving to a majority white school. After all, I am Native and from the same tribe. I expected there to be a kinship and shared understanding that would cut through most of the awkward getting-to-know-each-other phase. But that’s never how it played out. It did not matter where I came from. I was distrusted, tested, pushed away. Initially, I was consumed with contempt and resentment for perceived slights. And I was generally resigned to being unhappy. But then I learned some lessons that allowed me to cope with being an outsider. For example, respect is something earned not given based on background, race, sex, household income, or tribal affiliation. And virtues such as tolerance, generosity, self-regulation, patience, and resilience are absolute necessities to function in society. And finally, empathy and forgiveness are the keys to some semblance of inner peace and happiness.

And now I carry these lessons forward to my current position in the emergency department on the Navajo Nation. Again, I expect no special treatment due to my ethnicity, the letters after my name, or the beaded stethoscope around my neck. I never expect my words and recommendations to be taken at face value because of where I went to school and my training. I knew coming in as the outsider — the new guy — was going to be hard. I expected to be challenged and looked upon cautiously as I encountered each new face. And I believe that patients have a right to be just a little bit mistrusting of outsiders, Native or not, physician or not. Not to be flippant, but let’s face it, the historical record of Native people and outside influences is dismal. Not even the Indian Health Service — the organization bound by trust to care for the health and well-being of Native people — has a clean historical track record.

To illustrate, I want to tell a story about my aunty She-sheep. Her name is a phonetic form of our Anishinaabemowin nickname for her, zhiishiib, meaning duck (noun). I remember her vividly — her top dentures rattling around sometimes while she talked or smiled, her stout and doughy form, which calmed me when she held me close. Sometimes I would grab at the skin on the back of her arms and elbows, which I’m not sure she appreciated, but she protested little. And of course her gait, which, as you can guess, resembled that of a duck. Overall, I have such good memories of her. But as the rose-colored glasses with which we view memories become smudged with time, I learned something about her that shocked me.

My aunty She-sheep carried a great sadness despite her happy countenance. Her biggest regret was that she never had the big happy family she had always wanted. The reason was that right was taken from her, forcibly and with sinister motives. As she was going into labor, with her son of whom I know nothing about, the delivering physician and local priest took her husband, my great-uncle Dominick, aside and told him to sign a paper to consent for a cesarean. My great-uncle, illiterate and not sure of what he was signing, did not realize that he had just consented to a hysterectomy. This fact was hidden from my aunt who did not learn until years later after many failed attempts at pregnancy. I am not sure if this happened to any other women in my family but I know that my great-aunt was not the only Native woman to be sterilized without her informed consent.

In 1976 the Government Accountability Office (GAO) released a report confirming long-held suspicions that physicians were to blame for the declining birthrate amongst some tribes, and independent studies that followed estimated that as many as 1 in 4 women were sterilized without consent or under significant unethical and coercive practices.[1]  These practices were carried out by physicians, some employed by the Indian Health Service, who took the same oath as all physicians do to protect and hold sacred the values, beliefs and well-being of our patients. And, like in the case of my aunty She-sheep, many did so with the assistance of local clergy.

Now I can understand, appreciate and empathize with Native people and the distrust of outsiders. As I think on my chosen career and the tragedy of aunty She-sheep, I wonder if she would have been disappointed in me. After all, I have become part of the very establishment and profession that stole her dream. Would she welcome me into her arms as lovingly as she always did or keep me at arm’s length while looking upon me with suspicion and distrust?  Of course, I know her reaction would be the former. She learned it is our capacity for love, compassion, and forgiveness which allows us to find joy in this world. She would be proud of me, because I have the opportunity to make a positive influence in the lives of patients and Native communities.  She would encourage me to be the caring and compassionate physician that she never had. She would be sure that I would never engage, bear witness, or tolerate any mistreatment of Native people or any patient for that matter. Finally, I know she would want me to redouble my efforts to further a dialogue to understand and help heal those past injustices. By the way, I just thought of another thing I am thankful for — this forum, which gives me an opportunity to reflect on those efforts.

Because of my Aunty She-sheep’s story and my childhood as an outsider, I can understand why we — as a nation, or just as people who have suffered irreplaceable loss at the hands of others with different beliefs and backgrounds — have a distrust of outsiders. We hurt and resent until we find comfort in closing ourselves off, shutting down our borders.  But She-sheep knew better. There were bad doctors who ignored their oath and mistreated their patients. But far outnumbering those individuals are incredible doctors who have dedicated their lives to improving the quality of life of their patients. In fact, in the ultimate display of forgiveness and love, she nurtured one, my mother, who then went on to nurture me. And with our time’s recent events and today’s fears of terrorism and refugee flights, I see parallels and sadly repeated mistakes of the past. Yes, there are some horribly destructive, selfish, and misguided people who have committed atrocious crimes against others, but they are the exception. We cannot allow our compassion, generosity, and kindness to be blighted or smothered because of the actions of the terrible few.

The majority of people seeking safety and asylum, are, like you and me, looking for home — a place where they can become part of a community, raise their families without fear and invest in a future for their loved ones. They are outsiders, as all of us have felt at some time or another, adjusting to circumstances beyond their control. All they want is to be accepted, be productive, be happy. I have just one more thing to be thankful for.  I am thankful for people like my Aunty She-sheep, whose story I now share, whose example I now follow and whose expectations I now try to live up to.  I ask that others follow, let go of that resentment and fear. During this holiday season open your hearts and minds, and create some space for dialogue and forgiveness rather than vitriol and bitterness. Then, maybe we all can find a little more peace and happiness.

[1] J. Lawrence, “The Indian Health Service and the Sterilization of Native American Women,”American Indian Quarterly 24 (2000): 400-419.

 

 

 

Risks for Second Cancer After Hodgkin’s Lymphoma Therapy

Posted by James Yeh, M.D. M.P.H. • December 23rd, 2015

Second Cancer Risk Up to 40 Years after Treatment for Hodgkin’s LymphomaYou are meeting Mrs. Mason in your primary care clinic for the first time today. She has a history of Hodgkin’s lymphoma and was treated with chemotherapy and radiation therapy over 25 years ago. You wonder what is her risk for additional cancers as a result of treatment for Hodgkin’s lymphoma?

While the use of radiation therapy and alkylating agents in the chemotherapy regime for Hodgkin’s lymphoma have resulted in high rates of survival, these individuals also experience higher risks of secondary solid cancers than the average population due to treatment side effects. Hodgkin’s lymphoma treatments have evolved to reduce this risk of acquiring secondary solid cancers.

In a study recently published in NEJM, the authors asked whether the kind of treatments that have been implemented since the late 1980s, with lower radiation doses, smaller radiation target fields, and less toxic chemotherapy, have had an impact on the risk of developing a second cancer.

The authors assessed a cohort of 3905 patients in the Netherlands with Hodgkin’s lymphoma who had survived for at least 5 years. This group of patients were initially treated at seven academic medical centers and hospitals between 1965 and 2000. The patients were 15 to 51 years old at the time of the treatment. The primary outcome was the incidence risk of second cancer.

About 61% of patients had received combined modality therapy with chemotherapy and radiation therapy with the remaining receiving either radiation only (27%) or chemotherapy only (12%). With a median follow-up of about 19 years, about a quarter of the cohort (n=908) developed 1,055 second cancers.

Compared to the general population, the risk of a second cancer was more than four times greater (4.6-fold, 95% CI 4.3-4.9) in patients with Hodgkin’s lymphoma. This resulted in 122 excess cancers per 10,000 person-years. Notably, the second cancer risk was not lower in patients treated in the most recent calendar period studied (1989 to 2000) compared to patients treated in earlier periods.

This risk continued to be elevated even 35 years after the initial treatment, and by 40 years, nearly 50% of the patients had a second cancer. The highest absolute excess risks were seen for cancers of the lung, breast, GI-tract, and non-Hodgkin’s lymphoma. Although lower risk of breast cancer was associated with the use of smaller radiation fields when compared to mantle field radiotherapy, breast cancer risk continues to remain elevated in the most recent period studied when less extensive radiotherapy was used.

In a NEJM editorial, Radford and Longo note that “with respect to stomach, pancreas and colorectal cancers, the authors found that the greatest risk was associated with previous infra-diaphragmatic radiotherapy and/or procarbazine containing chemotherapy for which a dose response effect was observed. Procarbazine was also implicated in the increased risk of non-Hodgkin’s lymphomas.”

What did we learn from this study? We learned that the risk of developing second cancers remain elevated despite changes over time in the treatment of Hodgkin’s lymphoma. Clinicians who take care of survivors of Hodgkin’s lymphoma should be vigilant of second cancer risks.

At the end of the visit with Mrs. Mason, you ordered screening tests for breast, lung, and colon cancers. You also look up the guidelines on surveillance care on the National Comprehensive Cancer Network and on the American Society of Clinical Oncology websites. Which cancer screening tests should be ordered for Hodgkin’s lymphoma survivors? When should these screening tests start? 

Ibrutinib as Initial Therapy for CLL

Posted by Carla Rothaus • December 18th, 2015

Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic LeukemiaThe Bruton’s tyrosine kinase inhibitor ibrutinib was compared with the alkylating agent chlorambucil in patients with chronic lymphocytic leukemia. In a new Original Article, ibrutinib was associated with a higher response rate, longer duration of response, and longer overall survival.

Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in Western countries; it affects primarily older persons, with a median age at diagnosis of 72 years. Chlorambucil has been a standard first-line therapy in CLL, especially for older patients or those with coexisting conditions. Until recently, no treatment was clearly superior to chlorambucil in this population. Findings from multiple recent studies suggest a role for single-agent ibrutinib as initial treatment in patients with CLL. Burger et al. conducted a multicenter, open-label, randomized phase 3 trial to evaluate the efficacy and safety of single-agent ibrutinib as compared with chlorambucil in patients 65 years of age or older with previously untreated CLL.

Clinical Pearls

• What are some of the limitations of current first-line therapies for CLL?

All current standards for first-line CLL therapy are based on cytotoxic chemotherapy, including alkylating agents, purine analogues, or combinations thereof, except for patients with chromosome 17p13.1 deletion, for whom ibrutinib is a primary consideration for first-line therapy according to consensus guidelines. In addition to their myelosuppressive effects, these cytotoxic chemotherapy approaches may be associated with expansion of subclones with high-risk genetic abnormalities (e.g., TP53 or NOTCH1 mutation) and an increased risk of secondary cancers, including treatment-related myelodysplasia and acute myeloid leukemia.

• Is progression-free survival prolonged with the use of ibrutinib as compared to chlorambucil in patients 65 years of age or older with previously untreated CLL?

In the study by Burger et al., ibrutinib resulted in significantly longer progression-free survival than that with chlorambucil (median, not reached vs. 18.9 months) as assessed by the independent review committee, with a relative risk of progression or death that was 84% lower than that with chlorambucil (hazard ratio, 0.16; 95% confidence interval [CI], 0.09 to 0.28; P<0.001). The rate of progression-free survival at 18 months was 90% in the ibrutinib group versus 52% in the chlorambucil group. The results of the analysis of progression-free survival were consistent in the higher-risk subgroups, including patients with advanced-stage cancer, higher ECOG performance-status score, presence of chromosome 11q22.3 deletion, and nonmutated IGHV status.

Figure 1. Progression-free Survival with Ibrutinib versus Chlorambucil.

Morning Report Questions

Q: How do overall survival and response rates compare among patients 65 years of age or older with previously untreated CLL who receive ibrutinib as compared to chlorambucil?

A: In the study by Burger et al., ibrutinib significantly prolonged overall survival (median, not reached in either group). The overall survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death with ibrutinib that was 84% lower than that with chlorambucil (hazard ratio, 0.16; 95% CI, 0.05 to 0.56; P=0.001). The response rate as assessed by the independent review committee was significantly higher in the ibrutinib group than in the chlorambucil group (86% vs. 35%). Furthermore, ibrutinib-treated patients had a restoration of bone marrow function, with a significantly higher rate of sustained improvement in hematologic variables.

Figure 2. Overall Survival and Response Rates with Ibrutinib versus Chlorambucil.

Figure 3. Hematologic Variables over Time in the Safety Population.

Q: What adverse events were associated with ibrutinib in the Burger study?

A: The safety of ibrutinib in this older population of patients with CLL who often had clinically significant coexisting conditions was consistent with that in previous reports. Exposure to treatment and adverse-event follow-up was nearly 2.5 times as long with ibrutinib as with chlorambucil. In the ibrutinib group, diarrhea was the most frequent adverse event (in 42% of the patients, including grade 3 diarrhea in 4%). Other adverse events that occurred in 20% of the patients in the ibrutinib group were fatigue, nausea, and cough. Similar to findings in previous reports about ibrutinib, major hemorrhage was observed in 4% of the patients, with no fatal events, and atrial fibrillation occurred in 6%, with the majority of the events (in six of eight patients) being grade 2 events that were observed over the period of 1.5 years while the patients were taking ibrutinib. Hypertension was reported more frequently with ibrutinib than with chlorambucil, with no events leading to dose modification or having a severity of grade 4 or 5. The rates of fatigue, nausea, vomiting, and myelosuppression were higher with chlorambucil than with ibrutinib. Early discontinuation of treatment owing to adverse events was more than twice as frequent with chlorambucil as with ibrutinib.

Table 2. Adverse Events and Duration of Treatment.

Andexanet Alfa

Posted by Carla Rothaus • December 18th, 2015

Andexanet Alfa for the Reversal of Factor XaThe new oral anticoagulants have many advantages over warfarin, but one disadvantage is the inability to rapidly reverse their anticoagulant effects. Andexanet, a small-molecule factor Xa fragment, rapidly lowered levels of rivaroxaban and apixaban in older healthy volunteers. A new Original Article summarizes. 

The direct factor Xa inhibitors apixaban, rivaroxaban, and edoxaban are used in the prevention and treatment of thromboembolism. In spite of the demonstrated safety and efficacy of factor Xa inhibitors, as well as their practical advantages over vitamin K antagonists such as warfarin, the lack of a specific antidote to reverse their anticoagulant effects is an important limitation. Andexanet alfa (andexanet) is a specific reversal agent that is designed to neutralize the anticoagulant effects of both direct and indirect factor Xa inhibitors. Two parallel trials were conducted — Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors Apixaban (ANNEXA-A) and Rivaroxaban (ANNEXA-R) — to establish the efficacy and safety of andexanet for the reversal of anticoagulation with apixaban or rivaroxaban in older healthy volunteers.

Clinical Pearls

• What is andexanet and how does it work?

Andexanet is a recombinant modified human factor Xa decoy protein that is catalytically inactive but that retains the ability to bind factor Xa inhibitors in the active site with high affinity and a 1:1 stoichiometric ratio. Andexanet binds and sequesters factor Xa inhibitors within the vascular space, thereby restoring the activity of endogenous factor Xa and reducing levels of anticoagulant activity, as assessed by measurement of thrombin generation and anti-factor Xa activity, the latter of which is a direct measure of the anticoagulant activity.

• Does andexanet reverse the anticoagulant effects of apixaban and rivaroxaban?

In the ANNEXA-A and ANNEXA-R studies, conducted in older healthy volunteers, anti-factor Xa activity was rapidly reduced (within 2 to 5 minutes) to a greater extent after administration of a bolus of andexanet than after administration of placebo, both in the apixaban study and in the rivaroxaban study. When andexanet was administered as a bolus plus a 2-hour infusion, it also reduced anti-factor Xa activity to a greater extent than did placebo, both in the apixaban study and in the rivaroxaban study.

Figure 1. Time Courses of Anti-Factor Xa Activity before and after Administration of Andexanet.

Morning Report Questions

Q: Is the use of andexanet associated with thrombotic events or other adverse events?

A: In the ANNEXA-A and ANNEXA-R studies, there were no serious or severe adverse events, and no thrombotic events were reported. Antibodies to factor X or factor Xa (measured through day 43) did not develop in any participants. Neutralizing antibodies against andexanet were not detected. onneutralizing antibodies against andexanet were detected in 1 of 44 participants (2%) who received placebo and in 17 of 101 participants (17%) who received andexanet (2 of these participants had nonneutralizing antibodies before andexanet administration). Antibodies tended to appear within 15 to 30 days after andexanet administration, and the titers were generally low (at or below 1:640) among the 18 positive participants, except in 1 participant (who had a titer of 1:2560). These results indicate that andexanet has little immunogenicity after a single intravenous exposure. D-Dimer and prothrombin fragments 1 and 2 were measured in all participants, and transient elevations were noted that generally returned to the normal range within 24 to 72 hours.

Table 1. Drug-Related Adverse Events.

Q: What is known about the efficacy of andexanet in patients who require urgent reversal of factor Xa inhibitor activity?

A: The ANNEXA-A and ANNEXA-R studies do not present data on the efficacy and safety of andexanet in patients who require urgent reversal of factor Xa inhibitor activity because of bleeding or for emergency surgery. Although the extent and duration of factor Xa inhibitor reversal that is required to achieve hemostasis in patients is unknown, studies in animals of the use of andexanet to control bleeding have shown that a reduction in anticoagulation markers, including anti-factor Xa activity and unbound inhibitor plasma concentration, was associated with a significant reduction in blood loss, which was evident within 10 to 15 minutes after administration of the study drug in these models. The ongoing ANNEXA-4 phase 3b-4 study (ClinicalTrials.gov number, NCT02329327) is evaluating the efficacy and safety of andexanet in patients with factor Xa inhibitor-associated acute major bleeding.

Andexanet Alpha for the Reversal of Factor Xa Inhibitor Activity

Posted by Andrea Merrill • December 14th, 2015

Andexanet Alfa for the Reversal of Factor XaAs a general surgery resident more than half-way through my training career, I have taken care of my fair share of trauma patients. However, the trauma patients I’m referring to aren’t the stereotypical victims of gun-shot and stab wounds seen on TV. One of my most common trauma patients is the frail 80-something year old woman on anti-coagulation for atrial fibrillation who fell down a few stairs and hit her head, chest or hip. In the past, most of these patients had been anti-coagulated with warfarin (Coumadin) which, although inconvenient, was able to be reversed with vitamin K or fresh frozen plasma (and more recently prothrombin complex concentrate) in emergency situations. Now though, many patients are being treated with the easier-to-use novel oral anti-coagulants (NOACs) such as direct thrombin inhibitors and factor Xa inhibitors that don’t require INR monitoring and frequent blood draws. While patients enjoy many of the benefits of NOACs, these newer agents came at a cost–the absence of a rapid reversal antidote can be deadly in the setting of trauma or bleeding.

Fortunately, recent clinical trials have shown efficacy for new antidotes to some of these NOACS. First a report on idarucizumab (Praxbind) for the reversal of dabigatran (Pradaxa), a direct thrombin inhibitor, was published in NEJM this past August. This has been followed by a report on andexanet alpha for the reversal of the factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eloquis), published Online First last month in NEJM by Siegal et al.

Andexanet alpha is a recombinant modified human factor Xa decoy protein that is able to bind to factor Xa inhibitors without interacting with other coagulation factors. Andexanet represents a novel approach to reversing NOACs. These proof-of-concept trials enrolled 145 healthy volunteers aged 50-75 and randomly assigned participants to receive a factor Xa inhibitor (apixiban or rivaroxaban) and either a placebo or andexanet (as a bolus or as a bolus plus 2 hour infusion).

Anti-factor Xa activity was rapidly reduced after administration of a bolus of andexanet in both apixaban and rivaroxaban groups as compared to placebo. The reversal lasted for about 2 hours, consistent with the known half-life of andexanet, before levels gradually increased to that of the placebo recipients. For the group receiving a bolus plus 2 hour infusion, andexanet had similar effect on restoration of factor Xa activity for andexanet compared to placebo. The effect lasted for 1-2 hours after completion of the infusion. All participants who received andexanet had an 80% or greater reversal of anti-factor Xa activity compared to none in the placebo group. There were no serious adverse events or thrombotic events reported.

There are several limitations to this study including a relatively young population with minimal comorbidities and normal creatinine. And although this represents a rigorous scientific study, it does not provide us with data regarding the real time use of andexanet in bleeding patients or patients undergoing emergency surgery. Additionally, as Jean Connors, from Brigham and Women’s Hospital, explains in the accompanying editorial, dosing of andexanet is not straight forward “potentially making use in the busy ER environment challenging, and concerning for under dosing the bleeding patient if clinically obtained information is incorrect.” “Despite these current knowledge limitations,” Dr. Connors concludes, “andexanet represents a giant step forward in our ability to control anticoagulation therapy.” NEJM Deputy Editor Dr. Dan Longo concurs adding, “Andexanet will likely be a useful tool for restoring hemostasis among patients on Factor Xa inhibitors who require immediate reversal. One unresolved issue is whether the development of non-neutralizing antibodies to andexanet among 16% of recipients will alter the agents’ pharmacology sufficiently to compromise efficacy should a second or subsequent event require repeated use.”

With a phase 3b/4 study underway to assess the clinical effectiveness of andexanet in patients on factor Xa inhibitors with major bleeding, we are moving closer to approval of another potential anti-coagulant reversal agent. Perhaps before I finish residency, there will be an FDA-approved reversal agent available for me to give to my bleeding trauma patients on apixaban or rivaroxaban.

Apply for the NEJM Resident Program

Posted by Jennifer Zeis • December 14th, 2015

The New England Journal of Medicine is offering a two-week elective course for trainees and fellows PGY3 and higher who seek a deeper understanding of how a peer-review journal works and how editors make decisions about publishing papers.

It is a participatory elective based on the New England Journal of Medicine and taught at our editorial offices in Boston. This is a full-time course, including:

  • Lectures
  • Journal clubs
  • Attendance at editors’ meetings
  • Reading and writing assignments
  • Individual discussions/mentoring with Deputy Editors

The course will be held May 2 – 13, 2016. More details can be found with the application, where interested trainees and fellows should apply before 5:00 p.m. EST on Monday, January 11, 2016. Eight participants will be chosen at random from among qualified candidates.

A Man with Weight Loss

Posted by Carla Rothaus • December 11th, 2015

A 21-Year-Old Man with Fatigue and Weight LossIn a new Case Record of the Massachusetts General Hospital, a 21-year-old man was admitted to this hospital because of fatigue, weight loss, tender gynecomastia, hyperthyroidism, and lesions in the lungs and liver on radiographic imaging. Diagnostic procedures were performed.

Luteinizing hormone and human chorionic gonadotropin (hCG) are highly homologous and share the same receptor (the LH-hCG receptor). As compared with luteinizing hormone, hCG has a considerably longer circulating half-life and a more potent effect on the LH-hCG receptor, features that contribute to increased aromatase activity in Leydig cells. The net result of hCG stimulation is testicular production of both testosterone and estradiol, with subsequent inhibition of pituitary secretion of luteinizing hormone.

Clinical Pearls

• What types of tumors secrete hCG?

Germ-cell tumors are the neoplasms that are most likely to secrete hCG, but other nontrophoblastic tumors that originate in the lungs, liver, stomach, or kidneys have also been associated with ectopic hCG production.

• Among patients with hCG-secreting tumors, the prevalence of hyperthyroidism increases when the hCG level rises above what threshold?

HCG has low affinity for the thyrotropin receptor, and thyroid activity is correlated to hCG level. A very high hCG level, which can be present in persons who are pregnant or have certain tumors, may cause clinical manifestations of hyperthyroidism. In the absence of thyrotropin-receptor mutations, the combination of frank hyperthyroidism and undetectable thyrotropin levels is typically seen only when hCG levels are higher than 50,000 IU per liter. Several case series involving pregnant patients and patients with hCG-secreting tumors have shown that the prevalence of hyperthyroidism increases when the hCG level rises above the threshold of 50,000 IU per liter and that hyperthyroidism occurs in up to two thirds of patients with hCG levels higher than 200,000 IU per liter.

Figure 2. Pathogenesis of Human Chorionic Gonadotropin-Mediated Gynecomastia and Hyperthyroidism.

Morning Report Questions

Q: Do both pure seminomas and nonseminomatous germ-cell tumors produce hCG?

A: Germ-cell tumors are either pure seminomas or nonseminomatous germ-cell tumors. Seminomas do not commonly produce hCG, and if they do, the levels are typically lower than 1000 IU per liter. In contrast, approximately 20 to 40% of nonseminomatous germ-cell tumors produce hCG, and levels can exceed the threshold of 50,000 IU per liter. Most nonseminomatous germ-cell tumors are composed of a mix of different cell types, including elements of seminoma, choriocarcinoma, teratoma, yolk-sac tumor, and embryonal cancers. Choriocarcinoma elements are the most aggressive and most often associated with high secretion of hCG and no production of alpha-fetoprotein. Approximately 10% of germ-cell tumors are extragonadal. Several studies have shown that 3 to 5% of patients with nonseminomatous germ-cell tumors have high hCG levels and hyperthyroidism.

Q: What are some features of testicular choriocarcinoma?

A: In men, especially young men, choriocarcinoma is usually detected as a component of a testicular mixed germ-cell tumor and is exceedingly rare in its pure form. Choriocarcinoma has a propensity to metastasize to the central nervous system. In some orchiectomy specimens, metastatic choriocarcinoma appears only as a regressed germ-cell tumor. Choriocarcinoma is the germ-cell tumor that is most likely to have spontaneous regression because of its aggressive nature and tendency to outgrow the blood supply, but regression can be seen in seminomas and embryonal carcinomas. The diagnosis of choriocarcinoma is primarily based on the presence of intermixed mononuclear trophoblasts and syncytiotrophoblasts, a finding that distinguishes this tumor from other germ-cell tumors with only scattered syncytiotrophoblasts. Occasionally, persons with very high hCG levels have been noted to have hemorrhage from metastatic sites of choriocarcinoma, a feature that is referred to as the choriocarcinoma syndrome.

Thyroid Nodules

Posted by Carla Rothaus • December 11th, 2015

Thyroid Nodules for blogUltrasonography of the thyroid and ultrasonographically guided fine-needle aspiration can help determine whether a nodule is probably benign or malignant. In the absence of growth or suspicious clinical or radiologic findings, nodules with a benign finding on FNA can be monitored. A new Clinical Practice article summarizes.

Palpable thyroid nodules occur in approximately 4 to 7% of the population, but only about 8 to 16% of thyroid nodules harbor thyroid cancer.

Clinical Pearls

• What is a general approach to the evaluation of a newly discovered thyroid nodule?

An appropriate history includes questions relating to a history of head or neck irradiation and a family history of thyroid cancer. Physical examination should focus on the thyroid gland and lateral and central neck and should assess for supraclavicular and submandibular adenopathy. Serum thyrotropin levels should be measured routinely in a person with a thyroid nodule. All patients should undergo ultrasonography of the thyroid to document the number, size, and characteristics of thyroid nodules and to assess for the presence of cervical lymphadenopathy. Routine measurement of serum calcitonin has been suggested for the early detection of medullary thyroid carcinoma but is not recommended in the American Thyroid Association (ATA) guidelines.

Table 1. Clinical Findings Associated with an Increased Risk That a Thyroid Nodule Is Malignant.

• Under what circumstances is fine-needle aspiration of a thyroid nodule indicated?

Fine-needle aspiration, preferably performed under ultrasonographic guidance, is the most sensitive and cost-effective method to assess the nature of thyroid nodules and the need for surgery. The 2015 ATA guidelines recommend fine-needle aspiration for nodules 1 cm or larger in the greatest dimension that have a high- or intermediate-suspicion pattern on sonography, nodules 1.5 cm or larger that have a low-suspicion pattern on sonography, and nodules 2 cm or larger that have a very-low-suspicion pattern on sonography.

Figure 2. Ultrasonographic Images of Thyroid Nodules.

Figure 3. Thyroid Fine-Needle Aspiration Specimens.

Morning Report Questions

Q: How are cytologic results combined with clinical and ultrasonographic findings in the management of a thyroid nodule?

A: If the cytologic findings are interpreted as nondiagnostic, fine-needle aspiration should be repeated within 1 to 2 months in an effort to obtain sufficient cells for a more definitive diagnosis. A benign cytologic interpretation indicates a low likelihood of cancer and generally does not require repeat fine-needle aspiration unless suspicious features (e.g., increasing nodular size or enlarging cervical adenopathy) are noted during monitoring. When a sample is adequate and is evaluated by an experienced cytologist who documents a benign finding on fine-needle aspiration and there are no suspicious clinical or ultrasonographic findings, the authors generally recommend repeat ultrasonography in 1 to 2 years. For cases with suspicious sonographic features, an indeterminate fine-needle aspirate, or relevant adverse clinical history or physical examination findings, it is reasonable to perform repeat imaging earlier, in 6 to 12 months. If there is evidence of nodule growth (>50% change in volume or greater than or equal to 20% increase in at least two nodule dimensions with an increase of greater than or equal to 2 mm), a repeat fine-needle aspiration is recommended. False negative cytologic results occur in approximately 5 to 10% of cases overall, with higher rates reported for large nodules (11.7% for nodules greater than or equal to 3 cm vs. 4.8% for those <3 cm). Nodules with cytologic findings that are interpreted as malignant or “suspicious for malignancy” have a 94 to 100% and 53 to 97% chance, respectively, of being malignant (usually papillary thyroid cancer).

Table 2. Diagnostic Categories of Thyroid Nodules and Risk of Cancer.

Q: What is the potential value of molecular analysis of a fine-needle aspiration sample from a thyroid nodule?

A: Molecular analysis should be considered in the case of thyroid fine-needle aspiration results that are interpreted as atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) or follicular neoplasm or suspicious for a follicular neoplasm (FN/SFN). One molecular approach is to analyze the specimen by means of a gene-expression classifier to rule out cancer. In a report that assessed messenger RNA expression of 167 genes from fine-needle aspiration samples from nodules 1 cm or larger in diameter that were interpreted as indeterminate, the negative predictive value of the gene-expression classifier was 95% for AUS/ FLUS and 94% for FN/SFN, and the positive predictive value was 38% for AUS/FLUS and 37% for FN/SFN. These results suggest that, in general, patients with AUS/FLUS or FN/SFN whose results are negative on this molecular analysis can reasonably be monitored without immediate thyroidectomy. An alternative molecular approach is to directly assess the fine-needle aspirate for specific genetic abnormalities associated with thyroid cancer (including BRAF and RAS mutations, RET/PTC translocation and TERT promoter mutations for papillary thyroid cancer, and RAS and PIK3A mutations and PAX8-PPAR(gamma) translocation for follicular thyroid cancer). If the sample is positive for a BRAF mutation, the chance of cancer is close to 100%, and if the sample is positive for a RAS mutation, the chance of cancer is 80 to 90%.

Figure 1. Algorithm for Evaluation of Thyroid Nodules.