A study that characterized the occurrence and frequency of thrombocytopenia throughout the course of pregnancy found a significant decline in platelet counts during the course of pregnancy, and significant differences between pregnant and nonpregnant women. However, the study – published in the New England Journal of Medicine – also found that women with pregnancy-related complications were more likely to have platelet counts less than 150,000/mm³, even in the absence of known causes of thrombocytopenia.

Jessica Reese, PhD, and her coinvestigators at the University of Oklahoma, Oklahoma City, used data from pregnant women who delivered at a single site from 2011 to 2014. In all, 4,568 women from the study group had uncomplicated pregnancies, and 2,586 had pregnancy-related complications. To be included in the complicated pregnancy group, women needed a diagnosis of hypertension, diabetes, eclampsia or preeclampsia, or abnormal placentation. Another 197 women had preexisting disorders known to be associated with thrombocytopenia.

For the women with uncomplicated pregnancies, Dr. Reese and her colleagues compared platelet counts with those of nonpregnant women who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2012, using a stratified analysis that accounted for age and racial or ethnic background and excluding NHANES participants with cancer, diabetes, or hypertension.

To look at platelet levels across types of pregnancies and in comparison with nonpregnant women, the investigators established three cutpoints, grouping women into those who had a platelet count of at least 150,000/mm³, those with platelet counts less than 100,000/mm³ but at least 80,000/mm³, and those with platelet counts less than 80,000/mm³.

Only 1% of women with uncomplicated pregnancies had platelet counts less than 100,000/mm³ during pregnancy or at delivery, and just 5 women (0.1%) had unexplained platelet counts below 80,000/mm³. Seven more women with platelet counts less than 80,000/mm³ had an identified cause for their thrombocytopenia.

Overall, mean platelet counts were lower for the women with uncomplicated pregnancies during the first trimester than for nonpregnant women (251,000 vs. 273,000/mm³). These values fell throughout pregnancy to a mean of 217,000/mm³ by the time of delivery at a mean gestation of 39.0 weeks (P less than .001 for all time points). However, mean platelet counts rebounded by the time a postpartum value was obtained at a mean 7.1 weeks after delivery, to 264,000/mm³, a value that wasn’t significantly different from the nonpregnant cohort’s platelet counts.

When the investigators looked at mean platelet counts by trimester, they saw no difference between those with uncomplicated and complicated pregnancies until the third trimester. Then, “mean platelet counts decreased at a greater rate among women with pregnancy-related complications,” wrote Dr. Reese and her colleagues; 11.9% of women with complicated pregnancies had platelet counts below 150,000/mm³, while this level was seen in 9.9% of women without complications of pregnancy (P = .01).

At delivery, 2.3% (n = 59) of women with complicated pregnancies had platelet counts below 100,000/mm³, and 31 of these women had counts below 80,000/mm³, representing a significantly higher rate of thrombocytopenia at delivery than seen in the uncomplicated group (P less than .001).

In discussion, Dr. Reese and her coauthors examined the possible mechanisms for decreased levels of circulating platelets during pregnancy. Volume dilution from increased plasma volume is one well-accepted reason. Others include accumulation of platelets within the spleen, which increases in size by about 50% during pregnancy; similarly, the placenta’s circulation is similar to that of the spleen, so platelets may also accumulate there, the authors said. Further support for the placental mechanism comes from the lower average platelet counts for women with twin pregnancies.

The study’s relatively broad definition of pregnancy-related complications may have had the effect of lessening the difference in mean platelet counts between the complicated and uncomplicated pregnancy groups, the investigators acknowledged. Still, their study population had rates of these complications similar to those of the United States population, they said. “Therefore, our data may accurately reflect the platelet counts in women with these pregnancy-related complications,” they noted.

“Severe thrombocytopenia is rare, even in women with pregnancy-related complications,” concluded Dr. Reese and her colleagues. “Our data suggest that, for women with an uncomplicated pregnancy who have a platelet count of less than 100,000/mm³, a cause of thrombocytopenia other than the pregnancy itself should be considered.”

[email protected]

SOURCE: Reese J et al. N Engl J Med. 2018;379:32-43.

A study that characterized the occurrence and frequency of thrombocytopenia throughout the course of pregnancy found a significant decline in platelet counts during the course of pregnancy, and significant differences between pregnant and nonpregnant women. However, the study – published in the New England Journal of Medicine – also found that women with pregnancy-related complications were more likely to have platelet counts less than 150,000/mm³, even in the absence of known causes of thrombocytopenia.

Jessica Reese, PhD, and her coinvestigators at the University of Oklahoma, Oklahoma City, used data from pregnant women who delivered at a single site from 2011 to 2014. In all, 4,568 women from the study group had uncomplicated pregnancies, and 2,586 had pregnancy-related complications. To be included in the complicated pregnancy group, women needed a diagnosis of hypertension, diabetes, eclampsia or preeclampsia, or abnormal placentation. Another 197 women had preexisting disorders known to be associated with thrombocytopenia.

For the women with uncomplicated pregnancies, Dr. Reese and her colleagues compared platelet counts with those of nonpregnant women who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2012, using a stratified analysis that accounted for age and racial or ethnic background and excluding NHANES participants with cancer, diabetes, or hypertension.

To look at platelet levels across types of pregnancies and in comparison with nonpregnant women, the investigators established three cutpoints, grouping women into those who had a platelet count of at least 150,000/mm³, those with platelet counts less than 100,000/mm³ but at least 80,000/mm³, and those with platelet counts less than 80,000/mm³.

Only 1% of women with uncomplicated pregnancies had platelet counts less than 100,000/mm³ during pregnancy or at delivery, and just 5 women (0.1%) had unexplained platelet counts below 80,000/mm³. Seven more women with platelet counts less than 80,000/mm³ had an identified cause for their thrombocytopenia.

Overall, mean platelet counts were lower for the women with uncomplicated pregnancies during the first trimester than for nonpregnant women (251,000 vs. 273,000/mm³). These values fell throughout pregnancy to a mean of 217,000/mm³ by the time of delivery at a mean gestation of 39.0 weeks (P less than .001 for all time points). However, mean platelet counts rebounded by the time a postpartum value was obtained at a mean 7.1 weeks after delivery, to 264,000/mm³, a value that wasn’t significantly different from the nonpregnant cohort’s platelet counts.

When the investigators looked at mean platelet counts by trimester, they saw no difference between those with uncomplicated and complicated pregnancies until the third trimester. Then, “mean platelet counts decreased at a greater rate among women with pregnancy-related complications,” wrote Dr. Reese and her colleagues; 11.9% of women with complicated pregnancies had platelet counts below 150,000/mm³, while this level was seen in 9.9% of women without complications of pregnancy (P = .01).

At delivery, 2.3% (n = 59) of women with complicated pregnancies had platelet counts below 100,000/mm³, and 31 of these women had counts below 80,000/mm³, representing a significantly higher rate of thrombocytopenia at delivery than seen in the uncomplicated group (P less than .001).

In discussion, Dr. Reese and her coauthors examined the possible mechanisms for decreased levels of circulating platelets during pregnancy. Volume dilution from increased plasma volume is one well-accepted reason. Others include accumulation of platelets within the spleen, which increases in size by about 50% during pregnancy; similarly, the placenta’s circulation is similar to that of the spleen, so platelets may also accumulate there, the authors said. Further support for the placental mechanism comes from the lower average platelet counts for women with twin pregnancies.

The study’s relatively broad definition of pregnancy-related complications may have had the effect of lessening the difference in mean platelet counts between the complicated and uncomplicated pregnancy groups, the investigators acknowledged. Still, their study population had rates of these complications similar to those of the United States population, they said. “Therefore, our data may accurately reflect the platelet counts in women with these pregnancy-related complications,” they noted.

“Severe thrombocytopenia is rare, even in women with pregnancy-related complications,” concluded Dr. Reese and her colleagues. “Our data suggest that, for women with an uncomplicated pregnancy who have a platelet count of less than 100,000/mm³, a cause of thrombocytopenia other than the pregnancy itself should be considered.”

[email protected]

SOURCE: Reese J et al. N Engl J Med. 2018;379:32-43.

A study that characterized the occurrence and frequency of thrombocytopenia throughout the course of pregnancy found a significant decline in platelet counts during the course of pregnancy, and significant differences between pregnant and nonpregnant women. However, the study – published in the New England Journal of Medicine – also found that women with pregnancy-related complications were more likely to have platelet counts less than 150,000/mm³, even in the absence of known causes of thrombocytopenia.

Jessica Reese, PhD, and her coinvestigators at the University of Oklahoma, Oklahoma City, used data from pregnant women who delivered at a single site from 2011 to 2014. In all, 4,568 women from the study group had uncomplicated pregnancies, and 2,586 had pregnancy-related complications. To be included in the complicated pregnancy group, women needed a diagnosis of hypertension, diabetes, eclampsia or preeclampsia, or abnormal placentation. Another 197 women had preexisting disorders known to be associated with thrombocytopenia.

For the women with uncomplicated pregnancies, Dr. Reese and her colleagues compared platelet counts with those of nonpregnant women who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2012, using a stratified analysis that accounted for age and racial or ethnic background and excluding NHANES participants with cancer, diabetes, or hypertension.

To look at platelet levels across types of pregnancies and in comparison with nonpregnant women, the investigators established three cutpoints, grouping women into those who had a platelet count of at least 150,000/mm³, those with platelet counts less than 100,000/mm³ but at least 80,000/mm³, and those with platelet counts less than 80,000/mm³.

Only 1% of women with uncomplicated pregnancies had platelet counts less than 100,000/mm³ during pregnancy or at delivery, and just 5 women (0.1%) had unexplained platelet counts below 80,000/mm³. Seven more women with platelet counts less than 80,000/mm³ had an identified cause for their thrombocytopenia.

Overall, mean platelet counts were lower for the women with uncomplicated pregnancies during the first trimester than for nonpregnant women (251,000 vs. 273,000/mm³). These values fell throughout pregnancy to a mean of 217,000/mm³ by the time of delivery at a mean gestation of 39.0 weeks (P less than .001 for all time points). However, mean platelet counts rebounded by the time a postpartum value was obtained at a mean 7.1 weeks after delivery, to 264,000/mm³, a value that wasn’t significantly different from the nonpregnant cohort’s platelet counts.

When the investigators looked at mean platelet counts by trimester, they saw no difference between those with uncomplicated and complicated pregnancies until the third trimester. Then, “mean platelet counts decreased at a greater rate among women with pregnancy-related complications,” wrote Dr. Reese and her colleagues; 11.9% of women with complicated pregnancies had platelet counts below 150,000/mm³, while this level was seen in 9.9% of women without complications of pregnancy (P = .01).

At delivery, 2.3% (n = 59) of women with complicated pregnancies had platelet counts below 100,000/mm³, and 31 of these women had counts below 80,000/mm³, representing a significantly higher rate of thrombocytopenia at delivery than seen in the uncomplicated group (P less than .001).

In discussion, Dr. Reese and her coauthors examined the possible mechanisms for decreased levels of circulating platelets during pregnancy. Volume dilution from increased plasma volume is one well-accepted reason. Others include accumulation of platelets within the spleen, which increases in size by about 50% during pregnancy; similarly, the placenta’s circulation is similar to that of the spleen, so platelets may also accumulate there, the authors said. Further support for the placental mechanism comes from the lower average platelet counts for women with twin pregnancies.

The study’s relatively broad definition of pregnancy-related complications may have had the effect of lessening the difference in mean platelet counts between the complicated and uncomplicated pregnancy groups, the investigators acknowledged. Still, their study population had rates of these complications similar to those of the United States population, they said. “Therefore, our data may accurately reflect the platelet counts in women with these pregnancy-related complications,” they noted.

“Severe thrombocytopenia is rare, even in women with pregnancy-related complications,” concluded Dr. Reese and her colleagues. “Our data suggest that, for women with an uncomplicated pregnancy who have a platelet count of less than 100,000/mm³, a cause of thrombocytopenia other than the pregnancy itself should be considered.”

[email protected]

SOURCE: Reese J et al. N Engl J Med. 2018;379:32-43.

SAN DIEGO – Youth and young adults who have transitioned from prescription drug misuse to injection drug use tend to reside in dense social networks, results from a novel study suggest.

“A lot of what we know about the transition from prescription opioids to drug use is from populations that have already transitioned to injection drug use, and we’re asking them retrospectively to tell us about their use,” lead study author Alia Al-Tayyib, PhD, said in an interview at the annual meeting of the College on Problems of Drug Dependence.

Doug Brunk/MDedge News

[email protected]

SAN DIEGO – Youth and young adults who have transitioned from prescription drug misuse to injection drug use tend to reside in dense social networks, results from a novel study suggest.

“A lot of what we know about the transition from prescription opioids to drug use is from populations that have already transitioned to injection drug use, and we’re asking them retrospectively to tell us about their use,” lead study author Alia Al-Tayyib, PhD, said in an interview at the annual meeting of the College on Problems of Drug Dependence.

Doug Brunk/MDedge News

[email protected]

SAN DIEGO – Youth and young adults who have transitioned from prescription drug misuse to injection drug use tend to reside in dense social networks, results from a novel study suggest.

“A lot of what we know about the transition from prescription opioids to drug use is from populations that have already transitioned to injection drug use, and we’re asking them retrospectively to tell us about their use,” lead study author Alia Al-Tayyib, PhD, said in an interview at the annual meeting of the College on Problems of Drug Dependence.

Doug Brunk/MDedge News

[email protected]

Knowledge of the potential dangers of mixed martial arts is valuable for Department of Defense (DoD) health care providers as the military continues to implement combatives training into regular military instruction. This case study presents an active-duty service member who developed a spontaneous vertebral artery dissection (sVAD) during mixed martial arts training, which led to a cerebellar stroke.

To the authors’ knowledge this is the first documented case of a sVAD with associated stroke related to a mixed martial arts choke hold. Understanding the diagnosis, management, and prognosis of this condition will remain important as hand-to-hand combat instruction continues to be a part of regular military training.

Case Presentation

A 39-year-old active-duty male without significant past medical history presented to the emergency department (ED) at the San Antonio Military Medical Center in Texas for evaluation of severe vertigo with associated nausea and vomiting. He had participated in a Jiu-Jitsu match the evening prior to his presentation and reported that he was placed in a choke hold within the last 12 seconds of the match. He denied losing consciousness during this hold.

Once released, he attempted to stand and developed sudden onset vertigo with severe nausea, leading to multiple bouts of emesis. He additionally developed a throbbing, left-sided headache radiating down the left side of his neck. While the vertigo resolved within an hour, he continued to experience bouts of nausea and emesis, prompting him to present to the ED for further evaluation. The patient’s past medical history was remarkable only for multiple prior concussions, and his only medication was occasional ibuprofen. He denied the usage of recreational drugs.

Upon presentation to the ED, the patient’s vital signs were 139/93 mm Hg blood pressure, 73 beats per minute heart rate, 16 breaths per minute respiration, 100% oxygen saturation on room air, and 97.7° F temperature. 

The patient demonstrated normal balance and exhibited no nystagmus or limb/truncal ataxia as evaluated with finger-to-nose/heel-to-shin testing and gait exam. Complete blood count, comprehensive metabolic panel, and coagulation panel all demonstrated no abnormalities. 

The patient was admitted to the hospital for symptom control and further monitoring. His headache and nausea were managed with medications, and he began antiplatelet therapy with aspirin 325 mg daily. Given the size of his cerebellar infarction, it was decided that he would be monitored in the hospital for 72 hours for the development of significant cerebellar edema. He remained stable throughout his hospitalization and had only a mild headache at the time of discharge.

The patient was last seen 3 months postinjury with no subjective complaints and a completely normal neurologic exam. The treatment plan for the patient is to continue aspirin for 6 months postinjury at which time a repeat CT will be performed to ensure resolution. He has been counseled to avoid heavy lifting and any activity with potential for sudden movement/force of the neck (grappling/wrestling, chiropractic manipulation, roller coasters, or sit-ups) until the repeat CT has been completed.

Discussion

Spontaneous vertebral artery and carotid artery dissections are collectively referred to as sCADs. Spontaneous cervical artery dissections are a rare condition with a higher incidence of internal carotid dissections than are VADs (1.72 vs 0.97 per 100,000 people).¹ In contrast to the general stroke population, patients with sCADs are typically younger (mean age 45.3 years); and more than half of the patients are male.^1,2

Spontaneous cervical artery dissections are typically characterized by subintimal tears of the vertebral artery leading to the accumulation of an intramural hematoma and creation of a “false lumen” in the arterial wall.³ A sVAD is more often found in the pars transversaria (V2; 35%) or atlas loop (V3; 34%) segments of the vertebral artery than in the prevertebral (V1; 20%) or intracranial (V4; 11%) segments.^3-5 The etiology of these injuries is thought to be minor trauma to the neck in the context of a likely underlying connective tissue disease, though no direct association with a particular disease has been shown.

Biopsy evaluation of the superficial temporal arteries of patients with sCADs have revealed pathologic changes of the media and adventitial layers, including vacuolar degeneration and capillary neoangiogenesis, which are not found in the arteries of control patients.⁵ Although definitive association with a known connective tissue disease is rare, angiographic evidence of fibromuscular dysplasia, a nonspecific marker of connective tissue disease, is noted in as many as 15% to 20% of patients.⁶ Consequently, routine connective tissue disease screening is not recommended in these patients. One study found that about 40% of sCAD patients can recall minor cervical trauma in the preceding month in comparison to only 10% of other patients with stroke, leading to the moniker of “bottoms-up” or “beauty-parlor strokes” for these injuries. The most common mechanisms of minor neck trauma causing sCADs include tennis and golf swings, yoga, and roller-coaster rides.^7,8

Usually symptomatic at presentation, the most frequently encountered sCAD symptoms are head or neck pain (80%), brain ischemia (56%), and Horner syndrome (25%).¹ A study of 161 consecutive patients with internal carotid (n = 135) or vertebral artery (n = 26) dissections revealed that headache was reported by 69% of those with sVADs, and when present, was the initial manifestation in 33%. Headaches typically were ipsilateral to the dissection, located posteriorly in 83% of patients, and lasted an average duration of 72 hours. Neck pain, which was noted in 46% of sVAD patients, was predominantly posterior and ipsilateral in location as well.⁹ Ischemic symptoms of sVAD may include posterior circulation symptoms, such as vertigo, ataxia, diplopia, and leg weakness as well as lateral medullary (Wallenberg) syndrome characterized by dizziness, postural instability, limb hypotonia/ataxia, blurred vision, and nystagmus.

In a study of 169 patients with sCAD, brain ischemia occurred in 77% (131 patients) including 67% (n = 114) with ischemic stroke and 10% (n = 17) with transient ischemic attack. Head and/or neck pain was noted in 88% of those with brain ischemia.⁴ Etiologies for infarction included thromboembolic (85%), hemodynamic (12%), and mixed (3%).¹⁰ Isolated local symptoms are rare with one study of 245 patients with sCAD revealing only 20 (8%) presenting with pain only. Of those with pain only, 6 presented with headache, 2 with neck pain, and 12 with both.¹¹

Diagnosis of sVAD requires a high index of suspicion and is confirmed by diagnostic testing. Previously, invasive angiography was the diagnostic gold standard, but with the improvement in quality of CT and MR angiography, these noninvasive modalities have become the tests of choice. There have been no studies to date revealing a definitive benefit of one modality over the other. A meta-analysis of 25 articles that compared the use of CT and MR angiography for the diagnosis of carotid and VAD revealed similar sensitivity and specificity.¹² In contrast, a study involving 10 patients with confirmed sVAD who had both CT and MR angiographies during evaluation showed more total findings consistent with dissection on CT than with MR angiography when graded by 2 neuroradiologists. Additionally, the neuroradiologists subjectively rated CT angiography as preferential to MR in showing the imaging findings of dissection in 8 of 10 cases of vertebral dissection.¹³

Treatment for sCAD remains heavily debated. The use of IV thrombolysis within the standard time window for acute ischemic stroke is advocated for these patients. A meta-analysis of patients with sCAD vs matched patients with stroke from other causes treated with IV thrombolysis showed no difference in mortality at 3 months (9.0% vs 8.8%) or symptomatic intracranial hemorrhage (3.3% vs 3.0%). Additionally, similar percentages of patients had excellent (30.9% vs 37.4%) and favorable (58.2% vs 52.2%) 3-month functional statuses as expressed by the Modified Rankin Score (mRS).^14,15

Debate remains regarding subacute therapy for sCAD with either antiplatelet or anticoagulant therapy. A randomized study of 250 patients with cervical artery dissection (118 carotid, 132 vertebral) in which 126 patients were assigned to antiplatelet therapy and 124 patients were assigned to anticoagulant therapy showed an overall low rate of recurrent stroke (2%). There was no significant difference in efficacy between the therapy groups with stroke or death occurring in 3 antiplatelet patients and 1 anticoagulated patient. Adverse effects were very low in both groups with no deaths and only 1 major bleed in the anticoagulation group. Of note, stroke rates were lower in this study than prior observational studies.¹⁶

A nonrandomized study of 88 patients with extracranial sCAD showed overall low rates of recurrent ischemic stroke at 3 months with 1/59 (1.7%) in the antiplatelet group and 1/28 (3.6%) in the anticoagulation group (P 17 Given this low overall rate of recurrent stroke in prior studies, a guideline recommendation for antiplatelet or anticoagulant therapy cannot be made at this time.

The overall prognosis for this condition is fair. Functional status and recurrence risk are favorable, with one study finding a mRS score of 1 Additionally, a historic cohort study of 432 patients with first event of sCAD revealed that after a mean follow-up of 31 months, only 4 (0.9%) patients had a recurrent ischemic stroke either due to incomplete recanalization of the artery (n = 2) or recurrent sCAD (n = 2), and only 4 (0.9%) total recurrences of sCAD were report (2 without associated ischemic strokes).¹⁸ Further, a prospective study of 61 patients with confirmed sVAD revealed complete recanalization of 45.9% at 3 months, 62.3% at 6 months, and 63.9% at 12 months, suggesting that recanalization occurs mostly during the initial 6 months. There was no identified association between outcome and complete recanalization with favorable outcomes observed in 55 (90.2%) of patients and no further ischemic symptoms during follow-up.¹⁹

Neck maneuvers have been cited as a more common cause of sCAD in several previous studies. One retrospective study found chiropractic neck manipulation to be the etiology in 12 of 141 patients with CT- or MR- confirmed sCAD.²⁰ As noted previously, to the authors’ knowledge this is the first reported case of a sVAD occurring after a mixed martial arts choke hold. While sports-related strokes are rare, one evaluation of 70 published cases found that 80% were due to sCAD. Commonly associated sports in this study included football, yoga, wrestling, tennis, golf, and swimming.²¹ Grappling-related neck manipulation has been noted as an etiology in a few case reports.

Hyperextension of the neck was deemed to be the etiology in boys aged 11 years and 17 years who developed a sCAD while participating in Judo and backyard wrestling, respectively.^22,23 In the martial arts realm, there is a case report of a 26-year-old male who developed a sVAD after rapid head turning during a solo Kung Fu maneuver as well as a report of a 41-year-old male experiencing a right VAD complicated by a posterior infarction several days after straining his neck during a mixed martial arts competition.^24,25 The patient denied any choke hold or direct blow to the neck.

The present case is different in that it is the first reported case of a sVAD occurring after a submission maneuver. Prior grappling-related sVADs were associated with hyperextension or rapid acceleration/deceleration forces on the neck. Isometric force to the neck is a rarely described mechanism for development of this injury. Although there are isolated and infrequent forensic case reports of carotid dissection with strangulation injuries, the authors believe this is the first documented case of a sVAD attributed to a combatives submission.

In the context of the military health system, it is important to be aware of this potential complication of combatives as instruction in close-quarters combat continues to be an important part of military training.

Knowledge of the potential dangers of mixed martial arts is valuable for Department of Defense (DoD) health care providers as the military continues to implement combatives training into regular military instruction. This case study presents an active-duty service member who developed a spontaneous vertebral artery dissection (sVAD) during mixed martial arts training, which led to a cerebellar stroke.

To the authors’ knowledge this is the first documented case of a sVAD with associated stroke related to a mixed martial arts choke hold. Understanding the diagnosis, management, and prognosis of this condition will remain important as hand-to-hand combat instruction continues to be a part of regular military training.

Case Presentation

A 39-year-old active-duty male without significant past medical history presented to the emergency department (ED) at the San Antonio Military Medical Center in Texas for evaluation of severe vertigo with associated nausea and vomiting. He had participated in a Jiu-Jitsu match the evening prior to his presentation and reported that he was placed in a choke hold within the last 12 seconds of the match. He denied losing consciousness during this hold.

Once released, he attempted to stand and developed sudden onset vertigo with severe nausea, leading to multiple bouts of emesis. He additionally developed a throbbing, left-sided headache radiating down the left side of his neck. While the vertigo resolved within an hour, he continued to experience bouts of nausea and emesis, prompting him to present to the ED for further evaluation. The patient’s past medical history was remarkable only for multiple prior concussions, and his only medication was occasional ibuprofen. He denied the usage of recreational drugs.

Upon presentation to the ED, the patient’s vital signs were 139/93 mm Hg blood pressure, 73 beats per minute heart rate, 16 breaths per minute respiration, 100% oxygen saturation on room air, and 97.7° F temperature. 

The patient demonstrated normal balance and exhibited no nystagmus or limb/truncal ataxia as evaluated with finger-to-nose/heel-to-shin testing and gait exam. Complete blood count, comprehensive metabolic panel, and coagulation panel all demonstrated no abnormalities. 

The patient was admitted to the hospital for symptom control and further monitoring. His headache and nausea were managed with medications, and he began antiplatelet therapy with aspirin 325 mg daily. Given the size of his cerebellar infarction, it was decided that he would be monitored in the hospital for 72 hours for the development of significant cerebellar edema. He remained stable throughout his hospitalization and had only a mild headache at the time of discharge.

The patient was last seen 3 months postinjury with no subjective complaints and a completely normal neurologic exam. The treatment plan for the patient is to continue aspirin for 6 months postinjury at which time a repeat CT will be performed to ensure resolution. He has been counseled to avoid heavy lifting and any activity with potential for sudden movement/force of the neck (grappling/wrestling, chiropractic manipulation, roller coasters, or sit-ups) until the repeat CT has been completed.

Discussion

Spontaneous vertebral artery and carotid artery dissections are collectively referred to as sCADs. Spontaneous cervical artery dissections are a rare condition with a higher incidence of internal carotid dissections than are VADs (1.72 vs 0.97 per 100,000 people).¹ In contrast to the general stroke population, patients with sCADs are typically younger (mean age 45.3 years); and more than half of the patients are male.^1,2

Spontaneous cervical artery dissections are typically characterized by subintimal tears of the vertebral artery leading to the accumulation of an intramural hematoma and creation of a “false lumen” in the arterial wall.³ A sVAD is more often found in the pars transversaria (V2; 35%) or atlas loop (V3; 34%) segments of the vertebral artery than in the prevertebral (V1; 20%) or intracranial (V4; 11%) segments.^3-5 The etiology of these injuries is thought to be minor trauma to the neck in the context of a likely underlying connective tissue disease, though no direct association with a particular disease has been shown.

Biopsy evaluation of the superficial temporal arteries of patients with sCADs have revealed pathologic changes of the media and adventitial layers, including vacuolar degeneration and capillary neoangiogenesis, which are not found in the arteries of control patients.⁵ Although definitive association with a known connective tissue disease is rare, angiographic evidence of fibromuscular dysplasia, a nonspecific marker of connective tissue disease, is noted in as many as 15% to 20% of patients.⁶ Consequently, routine connective tissue disease screening is not recommended in these patients. One study found that about 40% of sCAD patients can recall minor cervical trauma in the preceding month in comparison to only 10% of other patients with stroke, leading to the moniker of “bottoms-up” or “beauty-parlor strokes” for these injuries. The most common mechanisms of minor neck trauma causing sCADs include tennis and golf swings, yoga, and roller-coaster rides.^7,8

Usually symptomatic at presentation, the most frequently encountered sCAD symptoms are head or neck pain (80%), brain ischemia (56%), and Horner syndrome (25%).¹ A study of 161 consecutive patients with internal carotid (n = 135) or vertebral artery (n = 26) dissections revealed that headache was reported by 69% of those with sVADs, and when present, was the initial manifestation in 33%. Headaches typically were ipsilateral to the dissection, located posteriorly in 83% of patients, and lasted an average duration of 72 hours. Neck pain, which was noted in 46% of sVAD patients, was predominantly posterior and ipsilateral in location as well.⁹ Ischemic symptoms of sVAD may include posterior circulation symptoms, such as vertigo, ataxia, diplopia, and leg weakness as well as lateral medullary (Wallenberg) syndrome characterized by dizziness, postural instability, limb hypotonia/ataxia, blurred vision, and nystagmus.

In a study of 169 patients with sCAD, brain ischemia occurred in 77% (131 patients) including 67% (n = 114) with ischemic stroke and 10% (n = 17) with transient ischemic attack. Head and/or neck pain was noted in 88% of those with brain ischemia.⁴ Etiologies for infarction included thromboembolic (85%), hemodynamic (12%), and mixed (3%).¹⁰ Isolated local symptoms are rare with one study of 245 patients with sCAD revealing only 20 (8%) presenting with pain only. Of those with pain only, 6 presented with headache, 2 with neck pain, and 12 with both.¹¹

Diagnosis of sVAD requires a high index of suspicion and is confirmed by diagnostic testing. Previously, invasive angiography was the diagnostic gold standard, but with the improvement in quality of CT and MR angiography, these noninvasive modalities have become the tests of choice. There have been no studies to date revealing a definitive benefit of one modality over the other. A meta-analysis of 25 articles that compared the use of CT and MR angiography for the diagnosis of carotid and VAD revealed similar sensitivity and specificity.¹² In contrast, a study involving 10 patients with confirmed sVAD who had both CT and MR angiographies during evaluation showed more total findings consistent with dissection on CT than with MR angiography when graded by 2 neuroradiologists. Additionally, the neuroradiologists subjectively rated CT angiography as preferential to MR in showing the imaging findings of dissection in 8 of 10 cases of vertebral dissection.¹³

Treatment for sCAD remains heavily debated. The use of IV thrombolysis within the standard time window for acute ischemic stroke is advocated for these patients. A meta-analysis of patients with sCAD vs matched patients with stroke from other causes treated with IV thrombolysis showed no difference in mortality at 3 months (9.0% vs 8.8%) or symptomatic intracranial hemorrhage (3.3% vs 3.0%). Additionally, similar percentages of patients had excellent (30.9% vs 37.4%) and favorable (58.2% vs 52.2%) 3-month functional statuses as expressed by the Modified Rankin Score (mRS).^14,15

Debate remains regarding subacute therapy for sCAD with either antiplatelet or anticoagulant therapy. A randomized study of 250 patients with cervical artery dissection (118 carotid, 132 vertebral) in which 126 patients were assigned to antiplatelet therapy and 124 patients were assigned to anticoagulant therapy showed an overall low rate of recurrent stroke (2%). There was no significant difference in efficacy between the therapy groups with stroke or death occurring in 3 antiplatelet patients and 1 anticoagulated patient. Adverse effects were very low in both groups with no deaths and only 1 major bleed in the anticoagulation group. Of note, stroke rates were lower in this study than prior observational studies.¹⁶

A nonrandomized study of 88 patients with extracranial sCAD showed overall low rates of recurrent ischemic stroke at 3 months with 1/59 (1.7%) in the antiplatelet group and 1/28 (3.6%) in the anticoagulation group (P 17 Given this low overall rate of recurrent stroke in prior studies, a guideline recommendation for antiplatelet or anticoagulant therapy cannot be made at this time.

The overall prognosis for this condition is fair. Functional status and recurrence risk are favorable, with one study finding a mRS score of 1 Additionally, a historic cohort study of 432 patients with first event of sCAD revealed that after a mean follow-up of 31 months, only 4 (0.9%) patients had a recurrent ischemic stroke either due to incomplete recanalization of the artery (n = 2) or recurrent sCAD (n = 2), and only 4 (0.9%) total recurrences of sCAD were report (2 without associated ischemic strokes).¹⁸ Further, a prospective study of 61 patients with confirmed sVAD revealed complete recanalization of 45.9% at 3 months, 62.3% at 6 months, and 63.9% at 12 months, suggesting that recanalization occurs mostly during the initial 6 months. There was no identified association between outcome and complete recanalization with favorable outcomes observed in 55 (90.2%) of patients and no further ischemic symptoms during follow-up.¹⁹

Neck maneuvers have been cited as a more common cause of sCAD in several previous studies. One retrospective study found chiropractic neck manipulation to be the etiology in 12 of 141 patients with CT- or MR- confirmed sCAD.²⁰ As noted previously, to the authors’ knowledge this is the first reported case of a sVAD occurring after a mixed martial arts choke hold. While sports-related strokes are rare, one evaluation of 70 published cases found that 80% were due to sCAD. Commonly associated sports in this study included football, yoga, wrestling, tennis, golf, and swimming.²¹ Grappling-related neck manipulation has been noted as an etiology in a few case reports.

Hyperextension of the neck was deemed to be the etiology in boys aged 11 years and 17 years who developed a sCAD while participating in Judo and backyard wrestling, respectively.^22,23 In the martial arts realm, there is a case report of a 26-year-old male who developed a sVAD after rapid head turning during a solo Kung Fu maneuver as well as a report of a 41-year-old male experiencing a right VAD complicated by a posterior infarction several days after straining his neck during a mixed martial arts competition.^24,25 The patient denied any choke hold or direct blow to the neck.

The present case is different in that it is the first reported case of a sVAD occurring after a submission maneuver. Prior grappling-related sVADs were associated with hyperextension or rapid acceleration/deceleration forces on the neck. Isometric force to the neck is a rarely described mechanism for development of this injury. Although there are isolated and infrequent forensic case reports of carotid dissection with strangulation injuries, the authors believe this is the first documented case of a sVAD attributed to a combatives submission.

In the context of the military health system, it is important to be aware of this potential complication of combatives as instruction in close-quarters combat continues to be an important part of military training.

Knowledge of the potential dangers of mixed martial arts is valuable for Department of Defense (DoD) health care providers as the military continues to implement combatives training into regular military instruction. This case study presents an active-duty service member who developed a spontaneous vertebral artery dissection (sVAD) during mixed martial arts training, which led to a cerebellar stroke.

To the authors’ knowledge this is the first documented case of a sVAD with associated stroke related to a mixed martial arts choke hold. Understanding the diagnosis, management, and prognosis of this condition will remain important as hand-to-hand combat instruction continues to be a part of regular military training.

Case Presentation

A 39-year-old active-duty male without significant past medical history presented to the emergency department (ED) at the San Antonio Military Medical Center in Texas for evaluation of severe vertigo with associated nausea and vomiting. He had participated in a Jiu-Jitsu match the evening prior to his presentation and reported that he was placed in a choke hold within the last 12 seconds of the match. He denied losing consciousness during this hold.

Once released, he attempted to stand and developed sudden onset vertigo with severe nausea, leading to multiple bouts of emesis. He additionally developed a throbbing, left-sided headache radiating down the left side of his neck. While the vertigo resolved within an hour, he continued to experience bouts of nausea and emesis, prompting him to present to the ED for further evaluation. The patient’s past medical history was remarkable only for multiple prior concussions, and his only medication was occasional ibuprofen. He denied the usage of recreational drugs.

Upon presentation to the ED, the patient’s vital signs were 139/93 mm Hg blood pressure, 73 beats per minute heart rate, 16 breaths per minute respiration, 100% oxygen saturation on room air, and 97.7° F temperature. 

The patient demonstrated normal balance and exhibited no nystagmus or limb/truncal ataxia as evaluated with finger-to-nose/heel-to-shin testing and gait exam. Complete blood count, comprehensive metabolic panel, and coagulation panel all demonstrated no abnormalities. 

The patient was admitted to the hospital for symptom control and further monitoring. His headache and nausea were managed with medications, and he began antiplatelet therapy with aspirin 325 mg daily. Given the size of his cerebellar infarction, it was decided that he would be monitored in the hospital for 72 hours for the development of significant cerebellar edema. He remained stable throughout his hospitalization and had only a mild headache at the time of discharge.

The patient was last seen 3 months postinjury with no subjective complaints and a completely normal neurologic exam. The treatment plan for the patient is to continue aspirin for 6 months postinjury at which time a repeat CT will be performed to ensure resolution. He has been counseled to avoid heavy lifting and any activity with potential for sudden movement/force of the neck (grappling/wrestling, chiropractic manipulation, roller coasters, or sit-ups) until the repeat CT has been completed.

Discussion

Spontaneous vertebral artery and carotid artery dissections are collectively referred to as sCADs. Spontaneous cervical artery dissections are a rare condition with a higher incidence of internal carotid dissections than are VADs (1.72 vs 0.97 per 100,000 people).¹ In contrast to the general stroke population, patients with sCADs are typically younger (mean age 45.3 years); and more than half of the patients are male.^1,2

Spontaneous cervical artery dissections are typically characterized by subintimal tears of the vertebral artery leading to the accumulation of an intramural hematoma and creation of a “false lumen” in the arterial wall.³ A sVAD is more often found in the pars transversaria (V2; 35%) or atlas loop (V3; 34%) segments of the vertebral artery than in the prevertebral (V1; 20%) or intracranial (V4; 11%) segments.^3-5 The etiology of these injuries is thought to be minor trauma to the neck in the context of a likely underlying connective tissue disease, though no direct association with a particular disease has been shown.

Biopsy evaluation of the superficial temporal arteries of patients with sCADs have revealed pathologic changes of the media and adventitial layers, including vacuolar degeneration and capillary neoangiogenesis, which are not found in the arteries of control patients.⁵ Although definitive association with a known connective tissue disease is rare, angiographic evidence of fibromuscular dysplasia, a nonspecific marker of connective tissue disease, is noted in as many as 15% to 20% of patients.⁶ Consequently, routine connective tissue disease screening is not recommended in these patients. One study found that about 40% of sCAD patients can recall minor cervical trauma in the preceding month in comparison to only 10% of other patients with stroke, leading to the moniker of “bottoms-up” or “beauty-parlor strokes” for these injuries. The most common mechanisms of minor neck trauma causing sCADs include tennis and golf swings, yoga, and roller-coaster rides.^7,8

Usually symptomatic at presentation, the most frequently encountered sCAD symptoms are head or neck pain (80%), brain ischemia (56%), and Horner syndrome (25%).¹ A study of 161 consecutive patients with internal carotid (n = 135) or vertebral artery (n = 26) dissections revealed that headache was reported by 69% of those with sVADs, and when present, was the initial manifestation in 33%. Headaches typically were ipsilateral to the dissection, located posteriorly in 83% of patients, and lasted an average duration of 72 hours. Neck pain, which was noted in 46% of sVAD patients, was predominantly posterior and ipsilateral in location as well.⁹ Ischemic symptoms of sVAD may include posterior circulation symptoms, such as vertigo, ataxia, diplopia, and leg weakness as well as lateral medullary (Wallenberg) syndrome characterized by dizziness, postural instability, limb hypotonia/ataxia, blurred vision, and nystagmus.

In a study of 169 patients with sCAD, brain ischemia occurred in 77% (131 patients) including 67% (n = 114) with ischemic stroke and 10% (n = 17) with transient ischemic attack. Head and/or neck pain was noted in 88% of those with brain ischemia.⁴ Etiologies for infarction included thromboembolic (85%), hemodynamic (12%), and mixed (3%).¹⁰ Isolated local symptoms are rare with one study of 245 patients with sCAD revealing only 20 (8%) presenting with pain only. Of those with pain only, 6 presented with headache, 2 with neck pain, and 12 with both.¹¹

Diagnosis of sVAD requires a high index of suspicion and is confirmed by diagnostic testing. Previously, invasive angiography was the diagnostic gold standard, but with the improvement in quality of CT and MR angiography, these noninvasive modalities have become the tests of choice. There have been no studies to date revealing a definitive benefit of one modality over the other. A meta-analysis of 25 articles that compared the use of CT and MR angiography for the diagnosis of carotid and VAD revealed similar sensitivity and specificity.¹² In contrast, a study involving 10 patients with confirmed sVAD who had both CT and MR angiographies during evaluation showed more total findings consistent with dissection on CT than with MR angiography when graded by 2 neuroradiologists. Additionally, the neuroradiologists subjectively rated CT angiography as preferential to MR in showing the imaging findings of dissection in 8 of 10 cases of vertebral dissection.¹³

Treatment for sCAD remains heavily debated. The use of IV thrombolysis within the standard time window for acute ischemic stroke is advocated for these patients. A meta-analysis of patients with sCAD vs matched patients with stroke from other causes treated with IV thrombolysis showed no difference in mortality at 3 months (9.0% vs 8.8%) or symptomatic intracranial hemorrhage (3.3% vs 3.0%). Additionally, similar percentages of patients had excellent (30.9% vs 37.4%) and favorable (58.2% vs 52.2%) 3-month functional statuses as expressed by the Modified Rankin Score (mRS).^14,15

Debate remains regarding subacute therapy for sCAD with either antiplatelet or anticoagulant therapy. A randomized study of 250 patients with cervical artery dissection (118 carotid, 132 vertebral) in which 126 patients were assigned to antiplatelet therapy and 124 patients were assigned to anticoagulant therapy showed an overall low rate of recurrent stroke (2%). There was no significant difference in efficacy between the therapy groups with stroke or death occurring in 3 antiplatelet patients and 1 anticoagulated patient. Adverse effects were very low in both groups with no deaths and only 1 major bleed in the anticoagulation group. Of note, stroke rates were lower in this study than prior observational studies.¹⁶

A nonrandomized study of 88 patients with extracranial sCAD showed overall low rates of recurrent ischemic stroke at 3 months with 1/59 (1.7%) in the antiplatelet group and 1/28 (3.6%) in the anticoagulation group (P 17 Given this low overall rate of recurrent stroke in prior studies, a guideline recommendation for antiplatelet or anticoagulant therapy cannot be made at this time.

The overall prognosis for this condition is fair. Functional status and recurrence risk are favorable, with one study finding a mRS score of 1 Additionally, a historic cohort study of 432 patients with first event of sCAD revealed that after a mean follow-up of 31 months, only 4 (0.9%) patients had a recurrent ischemic stroke either due to incomplete recanalization of the artery (n = 2) or recurrent sCAD (n = 2), and only 4 (0.9%) total recurrences of sCAD were report (2 without associated ischemic strokes).¹⁸ Further, a prospective study of 61 patients with confirmed sVAD revealed complete recanalization of 45.9% at 3 months, 62.3% at 6 months, and 63.9% at 12 months, suggesting that recanalization occurs mostly during the initial 6 months. There was no identified association between outcome and complete recanalization with favorable outcomes observed in 55 (90.2%) of patients and no further ischemic symptoms during follow-up.¹⁹

Neck maneuvers have been cited as a more common cause of sCAD in several previous studies. One retrospective study found chiropractic neck manipulation to be the etiology in 12 of 141 patients with CT- or MR- confirmed sCAD.²⁰ As noted previously, to the authors’ knowledge this is the first reported case of a sVAD occurring after a mixed martial arts choke hold. While sports-related strokes are rare, one evaluation of 70 published cases found that 80% were due to sCAD. Commonly associated sports in this study included football, yoga, wrestling, tennis, golf, and swimming.²¹ Grappling-related neck manipulation has been noted as an etiology in a few case reports.

Hyperextension of the neck was deemed to be the etiology in boys aged 11 years and 17 years who developed a sCAD while participating in Judo and backyard wrestling, respectively.^22,23 In the martial arts realm, there is a case report of a 26-year-old male who developed a sVAD after rapid head turning during a solo Kung Fu maneuver as well as a report of a 41-year-old male experiencing a right VAD complicated by a posterior infarction several days after straining his neck during a mixed martial arts competition.^24,25 The patient denied any choke hold or direct blow to the neck.

The present case is different in that it is the first reported case of a sVAD occurring after a submission maneuver. Prior grappling-related sVADs were associated with hyperextension or rapid acceleration/deceleration forces on the neck. Isometric force to the neck is a rarely described mechanism for development of this injury. Although there are isolated and infrequent forensic case reports of carotid dissection with strangulation injuries, the authors believe this is the first documented case of a sVAD attributed to a combatives submission.

In the context of the military health system, it is important to be aware of this potential complication of combatives as instruction in close-quarters combat continues to be an important part of military training.

Bristol Myers Squibb

Real-world data suggest that apixaban poses a lower risk of bleeding than warfarin, but patients who receive lower doses of apixaban have an increased risk of all-cause mortality.

Compared to warfarin, apixaban was associated with a decreased risk of major bleeding, intracranial bleeding, and gastrointestinal bleeding in certain patients.

Dabigatran and rivaroxaban were associated with a decreased risk of intracranial bleeding for certain patients, compared to warfarin.

However, patients who received rivaroxaban or lower doses of apixaban had an increased risk of all-cause mortality, compared to patients who received warfarin.

Yana Vinogradova, PhD, of University of Nottingham in the UK, and her colleagues reported these results in The BMJ.

The researchers set out to investigate the risks and benefits associated with apixaban, dabigatran, and rivaroxaban compared with warfarin in patients with and without atrial fibrillation (AF).

Using data from 2 large UK primary care databases, the researchers identified 196,061 patients who started or restarted anticoagulants (after more than a 12-month gap) between 2011 and 2016.

There were 132,231 patients taking warfarin, 7744 on dabigatran, 37,863 on rivaroxaban, and 18,223 on apixaban.

Slightly more than half of patients (53%, n=103,270) were diagnosed with AF, and 47% (n=92,791) were prescribed anticoagulants for other conditions.

When compared to warfarin in patients with AF, apixaban was associated with a decreased risk of:

• Major bleeding—adjusted hazard ratio [aHR]=0.66
• Intracranial bleeding—aHR=0.40.

In patients without AF, apixaban was associated with a decreased risk of:

• Major bleeding—aHR=0.60
• Any gastrointestinal bleeding—aHR=0.55
• Upper gastrointestinal bleeding—aHR=0.55.

In patients with AF, dabigatran was associated with a decreased risk of intracranial bleeding—aHR=0.45—compared to warfarin.

In patients without AF, rivaroxaban was associated with a decreased risk of intracranial bleeding—aHR=0.54—compared to warfarin.

Compared to patients taking warfarin, there was an increased risk of all-cause mortality for patients:

• With AF taking rivaroxaban—aHR=1.19
• Without AF taking rivaroxaban— aHR=1.51
• With AF taking lower doses of apixaban—aHR=1.27
• Without AF taking lower doses of apixaban—aHR=1.34.

The researchers said the increased risk of all-cause mortality in these patients may reflect the fact that patients taking warfarin are monitored more closely, or it may be related to underlying conditions.

The team did point out that this is an observational study, so no firm conclusions can be drawn about cause and effect. They also outlined some limitations, such as possible misclassification due to patients not taking their medication.

Nevertheless, the researchers concluded that “the risk of major bleeding is lower in apixaban users, regardless of the reason for prescribing, appearing to show apixaban to be the safest drug.”

Bristol Myers Squibb

Real-world data suggest that apixaban poses a lower risk of bleeding than warfarin, but patients who receive lower doses of apixaban have an increased risk of all-cause mortality.

Compared to warfarin, apixaban was associated with a decreased risk of major bleeding, intracranial bleeding, and gastrointestinal bleeding in certain patients.

Dabigatran and rivaroxaban were associated with a decreased risk of intracranial bleeding for certain patients, compared to warfarin.

However, patients who received rivaroxaban or lower doses of apixaban had an increased risk of all-cause mortality, compared to patients who received warfarin.

Yana Vinogradova, PhD, of University of Nottingham in the UK, and her colleagues reported these results in The BMJ.

The researchers set out to investigate the risks and benefits associated with apixaban, dabigatran, and rivaroxaban compared with warfarin in patients with and without atrial fibrillation (AF).

Using data from 2 large UK primary care databases, the researchers identified 196,061 patients who started or restarted anticoagulants (after more than a 12-month gap) between 2011 and 2016.

There were 132,231 patients taking warfarin, 7744 on dabigatran, 37,863 on rivaroxaban, and 18,223 on apixaban.

Slightly more than half of patients (53%, n=103,270) were diagnosed with AF, and 47% (n=92,791) were prescribed anticoagulants for other conditions.

When compared to warfarin in patients with AF, apixaban was associated with a decreased risk of:

• Major bleeding—adjusted hazard ratio [aHR]=0.66
• Intracranial bleeding—aHR=0.40.

In patients without AF, apixaban was associated with a decreased risk of:

• Major bleeding—aHR=0.60
• Any gastrointestinal bleeding—aHR=0.55
• Upper gastrointestinal bleeding—aHR=0.55.

In patients with AF, dabigatran was associated with a decreased risk of intracranial bleeding—aHR=0.45—compared to warfarin.

In patients without AF, rivaroxaban was associated with a decreased risk of intracranial bleeding—aHR=0.54—compared to warfarin.

Compared to patients taking warfarin, there was an increased risk of all-cause mortality for patients:

• With AF taking rivaroxaban—aHR=1.19
• Without AF taking rivaroxaban— aHR=1.51
• With AF taking lower doses of apixaban—aHR=1.27
• Without AF taking lower doses of apixaban—aHR=1.34.

The researchers said the increased risk of all-cause mortality in these patients may reflect the fact that patients taking warfarin are monitored more closely, or it may be related to underlying conditions.

The team did point out that this is an observational study, so no firm conclusions can be drawn about cause and effect. They also outlined some limitations, such as possible misclassification due to patients not taking their medication.

Nevertheless, the researchers concluded that “the risk of major bleeding is lower in apixaban users, regardless of the reason for prescribing, appearing to show apixaban to be the safest drug.”

Bristol Myers Squibb

Real-world data suggest that apixaban poses a lower risk of bleeding than warfarin, but patients who receive lower doses of apixaban have an increased risk of all-cause mortality.

Compared to warfarin, apixaban was associated with a decreased risk of major bleeding, intracranial bleeding, and gastrointestinal bleeding in certain patients.

Dabigatran and rivaroxaban were associated with a decreased risk of intracranial bleeding for certain patients, compared to warfarin.

However, patients who received rivaroxaban or lower doses of apixaban had an increased risk of all-cause mortality, compared to patients who received warfarin.

Yana Vinogradova, PhD, of University of Nottingham in the UK, and her colleagues reported these results in The BMJ.

The researchers set out to investigate the risks and benefits associated with apixaban, dabigatran, and rivaroxaban compared with warfarin in patients with and without atrial fibrillation (AF).

Using data from 2 large UK primary care databases, the researchers identified 196,061 patients who started or restarted anticoagulants (after more than a 12-month gap) between 2011 and 2016.

There were 132,231 patients taking warfarin, 7744 on dabigatran, 37,863 on rivaroxaban, and 18,223 on apixaban.

Slightly more than half of patients (53%, n=103,270) were diagnosed with AF, and 47% (n=92,791) were prescribed anticoagulants for other conditions.

When compared to warfarin in patients with AF, apixaban was associated with a decreased risk of:

• Major bleeding—adjusted hazard ratio [aHR]=0.66
• Intracranial bleeding—aHR=0.40.

In patients without AF, apixaban was associated with a decreased risk of:

• Major bleeding—aHR=0.60
• Any gastrointestinal bleeding—aHR=0.55
• Upper gastrointestinal bleeding—aHR=0.55.

In patients with AF, dabigatran was associated with a decreased risk of intracranial bleeding—aHR=0.45—compared to warfarin.

In patients without AF, rivaroxaban was associated with a decreased risk of intracranial bleeding—aHR=0.54—compared to warfarin.

Compared to patients taking warfarin, there was an increased risk of all-cause mortality for patients:

• With AF taking rivaroxaban—aHR=1.19
• Without AF taking rivaroxaban— aHR=1.51
• With AF taking lower doses of apixaban—aHR=1.27
• Without AF taking lower doses of apixaban—aHR=1.34.

The researchers said the increased risk of all-cause mortality in these patients may reflect the fact that patients taking warfarin are monitored more closely, or it may be related to underlying conditions.

The team did point out that this is an observational study, so no firm conclusions can be drawn about cause and effect. They also outlined some limitations, such as possible misclassification due to patients not taking their medication.

Nevertheless, the researchers concluded that “the risk of major bleeding is lower in apixaban users, regardless of the reason for prescribing, appearing to show apixaban to be the safest drug.”

Micrograph showing myelofibrosis

New research indicates that JAK inhibitors may increase the risk of lymphoma in patients with myelofibrosis (MF).

The patients studied had a 15- to 25-fold higher risk of developing B-cell lymphoma if they received treatment with JAK inhibitors.

The researchers speculate that screening MF patients for a pre-existing B-cell clone before starting JAK inhibitor therapy may help prevent lymphoma development.

Heinz Gisslinger, MD, of the Medical University of Vienna in Austria, and his colleagues conducted this research and reported the findings in Blood.

“[W]e started noticing sporadic cases of lymphomas developing in patients being treated for myeloproliferative neoplasms and wanted to know if this phenomenon was connected to treatment,” Dr Gisslinger said.

Therefore, he and his colleagues assessed 626 patients receiving treatment for myeloproliferative neoplasms (MPNs) at the Medical University of Vienna.

The incidence of B-cell lymphoma was 5.8% (4/69) in patients treated with JAK inhibitors and 0.36% (2/557) in patients who did not receive JAK inhibitors. That amounts to a 16-fold increased risk of lymphoma in patients receiving JAK inhibitors.

When the researchers analyzed only patients with primary MF (n=216), the increased risk of B-cell lymphoma was even greater. The incidence of lymphoma was 9.68% (3/31) in patients treated with JAK inhibitors and 0.54% (1/185) in patients who did not receive JAK inhibitors.

That corresponds to a 19-fold increased risk of B-cell lymphoma in primary MF patients treated with JAK inhibitors. When the researchers adjusted for age, there was a 21-fold greater risk. When they adjusted for sex, the risk was 25 times higher.

In a second cohort of 929 MPN patients, the incidence of B-cell lymphoma was 3.51% (2/57) in patients who received JAK inhibitors and 0.23% (2/872) in patients who did not. This corresponds to a 15-fold increased risk of lymphoma in the JAK inhibitor recipients.

Lymphoma cases

In all, there were 6 patients who developed lymphoma after JAK inhibitor treatment. Five developed diffuse large B-cell lymphoma, and 1 had high-grade B-cell lymphoma not otherwise specified.

Four of the patients had primary MF, 1 had post-polycythemia vera MF, and 1 had post-essential thrombocythemia (ET) MF. Five patients had a JAK2V617F mutation, and 1 (the post-ET MF patient) had a CALR mutation.

All 6 patients had received treatment with ruxolitinib. One patient also received fedratinib.

B-cell clone

The researchers studied bone marrow samples from 54 of the 69 patients treated with JAK inhibitors in the first cohort. The team found a pre-existing B-cell clone in 3 of the 4 patients who developed lymphoma. Further investigation suggested this was the clone that later transformed into lymphoma.

The researchers also found an association between JAK inhibition and an increased frequency of aggressive B-cell lymphomas in mouse models.

“By replicating this link between this B-cell clone and aggressive lymphoma, we hope to speed the discovery of an alternative therapy for myelofibrosis,” said study author Veronica Sexl, MD, of the University of Veterinary Medicine in Vienna. “These findings are going to be valuable in clinical care.”

“We determined that patients with this pre-existing B-cell clone in their bone marrow are most at risk for developing aggressive lymphoma,” added study author Ulrich Jäger, MD, of the Medical University of Vienna.

“We also know that up to 16% of people with myelofibrosis have immunoglobulin gene rearrangements like this B-cell clone. Therefore, our findings suggest that all patients with myelofibrosis should be tested for such gene rearrangements before prescribing JAK inhibitors to treat their disease.”

Micrograph showing myelofibrosis

New research indicates that JAK inhibitors may increase the risk of lymphoma in patients with myelofibrosis (MF).

The patients studied had a 15- to 25-fold higher risk of developing B-cell lymphoma if they received treatment with JAK inhibitors.

The researchers speculate that screening MF patients for a pre-existing B-cell clone before starting JAK inhibitor therapy may help prevent lymphoma development.

Heinz Gisslinger, MD, of the Medical University of Vienna in Austria, and his colleagues conducted this research and reported the findings in Blood.

“[W]e started noticing sporadic cases of lymphomas developing in patients being treated for myeloproliferative neoplasms and wanted to know if this phenomenon was connected to treatment,” Dr Gisslinger said.

Therefore, he and his colleagues assessed 626 patients receiving treatment for myeloproliferative neoplasms (MPNs) at the Medical University of Vienna.

The incidence of B-cell lymphoma was 5.8% (4/69) in patients treated with JAK inhibitors and 0.36% (2/557) in patients who did not receive JAK inhibitors. That amounts to a 16-fold increased risk of lymphoma in patients receiving JAK inhibitors.

When the researchers analyzed only patients with primary MF (n=216), the increased risk of B-cell lymphoma was even greater. The incidence of lymphoma was 9.68% (3/31) in patients treated with JAK inhibitors and 0.54% (1/185) in patients who did not receive JAK inhibitors.

That corresponds to a 19-fold increased risk of B-cell lymphoma in primary MF patients treated with JAK inhibitors. When the researchers adjusted for age, there was a 21-fold greater risk. When they adjusted for sex, the risk was 25 times higher.

In a second cohort of 929 MPN patients, the incidence of B-cell lymphoma was 3.51% (2/57) in patients who received JAK inhibitors and 0.23% (2/872) in patients who did not. This corresponds to a 15-fold increased risk of lymphoma in the JAK inhibitor recipients.

Lymphoma cases

In all, there were 6 patients who developed lymphoma after JAK inhibitor treatment. Five developed diffuse large B-cell lymphoma, and 1 had high-grade B-cell lymphoma not otherwise specified.

Four of the patients had primary MF, 1 had post-polycythemia vera MF, and 1 had post-essential thrombocythemia (ET) MF. Five patients had a JAK2V617F mutation, and 1 (the post-ET MF patient) had a CALR mutation.

All 6 patients had received treatment with ruxolitinib. One patient also received fedratinib.

B-cell clone

The researchers studied bone marrow samples from 54 of the 69 patients treated with JAK inhibitors in the first cohort. The team found a pre-existing B-cell clone in 3 of the 4 patients who developed lymphoma. Further investigation suggested this was the clone that later transformed into lymphoma.

The researchers also found an association between JAK inhibition and an increased frequency of aggressive B-cell lymphomas in mouse models.

“By replicating this link between this B-cell clone and aggressive lymphoma, we hope to speed the discovery of an alternative therapy for myelofibrosis,” said study author Veronica Sexl, MD, of the University of Veterinary Medicine in Vienna. “These findings are going to be valuable in clinical care.”

“We determined that patients with this pre-existing B-cell clone in their bone marrow are most at risk for developing aggressive lymphoma,” added study author Ulrich Jäger, MD, of the Medical University of Vienna.

“We also know that up to 16% of people with myelofibrosis have immunoglobulin gene rearrangements like this B-cell clone. Therefore, our findings suggest that all patients with myelofibrosis should be tested for such gene rearrangements before prescribing JAK inhibitors to treat their disease.”

Micrograph showing myelofibrosis

New research indicates that JAK inhibitors may increase the risk of lymphoma in patients with myelofibrosis (MF).

The patients studied had a 15- to 25-fold higher risk of developing B-cell lymphoma if they received treatment with JAK inhibitors.

The researchers speculate that screening MF patients for a pre-existing B-cell clone before starting JAK inhibitor therapy may help prevent lymphoma development.

Heinz Gisslinger, MD, of the Medical University of Vienna in Austria, and his colleagues conducted this research and reported the findings in Blood.

“[W]e started noticing sporadic cases of lymphomas developing in patients being treated for myeloproliferative neoplasms and wanted to know if this phenomenon was connected to treatment,” Dr Gisslinger said.

Therefore, he and his colleagues assessed 626 patients receiving treatment for myeloproliferative neoplasms (MPNs) at the Medical University of Vienna.

The incidence of B-cell lymphoma was 5.8% (4/69) in patients treated with JAK inhibitors and 0.36% (2/557) in patients who did not receive JAK inhibitors. That amounts to a 16-fold increased risk of lymphoma in patients receiving JAK inhibitors.

When the researchers analyzed only patients with primary MF (n=216), the increased risk of B-cell lymphoma was even greater. The incidence of lymphoma was 9.68% (3/31) in patients treated with JAK inhibitors and 0.54% (1/185) in patients who did not receive JAK inhibitors.

That corresponds to a 19-fold increased risk of B-cell lymphoma in primary MF patients treated with JAK inhibitors. When the researchers adjusted for age, there was a 21-fold greater risk. When they adjusted for sex, the risk was 25 times higher.

In a second cohort of 929 MPN patients, the incidence of B-cell lymphoma was 3.51% (2/57) in patients who received JAK inhibitors and 0.23% (2/872) in patients who did not. This corresponds to a 15-fold increased risk of lymphoma in the JAK inhibitor recipients.

Lymphoma cases

In all, there were 6 patients who developed lymphoma after JAK inhibitor treatment. Five developed diffuse large B-cell lymphoma, and 1 had high-grade B-cell lymphoma not otherwise specified.

Four of the patients had primary MF, 1 had post-polycythemia vera MF, and 1 had post-essential thrombocythemia (ET) MF. Five patients had a JAK2V617F mutation, and 1 (the post-ET MF patient) had a CALR mutation.

All 6 patients had received treatment with ruxolitinib. One patient also received fedratinib.

B-cell clone

The researchers studied bone marrow samples from 54 of the 69 patients treated with JAK inhibitors in the first cohort. The team found a pre-existing B-cell clone in 3 of the 4 patients who developed lymphoma. Further investigation suggested this was the clone that later transformed into lymphoma.

The researchers also found an association between JAK inhibition and an increased frequency of aggressive B-cell lymphomas in mouse models.

“By replicating this link between this B-cell clone and aggressive lymphoma, we hope to speed the discovery of an alternative therapy for myelofibrosis,” said study author Veronica Sexl, MD, of the University of Veterinary Medicine in Vienna. “These findings are going to be valuable in clinical care.”

“We determined that patients with this pre-existing B-cell clone in their bone marrow are most at risk for developing aggressive lymphoma,” added study author Ulrich Jäger, MD, of the Medical University of Vienna.

“We also know that up to 16% of people with myelofibrosis have immunoglobulin gene rearrangements like this B-cell clone. Therefore, our findings suggest that all patients with myelofibrosis should be tested for such gene rearrangements before prescribing JAK inhibitors to treat their disease.”

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has granted regenerative medicine advanced therapy (RMAT) designation for romyelocel-L, a myeloid progenitor cell therapy that doesn’t require HLA matching.

Romyelocel-L (CLT-008) is being developed as prophylaxis for serious bacterial and fungal infections in patients with de novo acute myeloid leukemia (AML) who develop neutropenia while receiving induction chemotherapy.

The FDA grants RMAT designation to therapies intended to treat serious or life-threatening conditions if there is preliminary clinical evidence that the therapies could address unmet medical needs.

RMAT designation provides similar advantages as breakthrough therapy designation, including early interactions with the FDA to discuss potential ways to accelerate the development of a therapy toward regulatory approval.

The FDA granted romyelocel-L RMAT designation based on a randomized, phase 2 trial of newly diagnosed AML patients who received induction consisting of cytarabine and an anthracycline.

Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 7043).

The trial enrolled 163 AML patients and randomized them, on the first day of induction, to receive:

• Daily granulocyte colony-stimulating factor (G-CSF) starting on day 14 (n=84)
• Romyelocel-L (7.5 x 10⁶cells/kg) on day 9 plus daily G-CSF starting on day 14 (n=79).

Patients received G-CSF until neutrophil recovery to at least 500/µL.

Baseline characteristics were well balanced between the treatment arms.

There were 120 evaluable patients—59 in the romyelocel-L arm and 61 in the control arm.

The study’s primary endpoint was days in a febrile episode (DFE). The mean DFE from day 9 to 28 was 6.46 days in the romyelocel-L arm and 6.86 days in the control arm (P=0.350). The mean DFE for days 15 to 28 was 2.36 and 3.90, respectively (P=0.020).

The incidence of microbiologically or clinically diagnosed infection from day 9 to 28 was 35.6% in the romyelocel-L arm and 47.5% in the control arm, a decrease of 25% (P=0.089).

From day 15 to 28 the incidence of infection was 6.8% in the romyelocel-L arm and 27.9% in the control arm, a decrease of 76% (P=0.002).

There were no infectious deaths in the romyelocel-L arm but 2 deaths attributed to pneumonia in the control arm.

The mean hospital stay was 25.5 days in the romyelocel-L arm and 28.7 days in the control arm (P=0.002).

The proportion of patients with serious adverse events (AEs) was 14% in the romyelocel-L arm and 18% in the control arm. The proportion of patients with infectious serious AEs was 50% and 77%, respectively.

The most frequent treatment-emergent AEs (in the romyelocel-L and control arms, respectively) were febrile neutropenia (31.4% and 31%), diarrhea (25.7% and 32.4%), hypokalemia (31.4% and 25.4%), hypophosphatemia (21.4% and 23.9%), and pyrexia (22.9% and 22.5%).

There were no cases of graft-versus-host disease.  

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has granted regenerative medicine advanced therapy (RMAT) designation for romyelocel-L, a myeloid progenitor cell therapy that doesn’t require HLA matching.

Romyelocel-L (CLT-008) is being developed as prophylaxis for serious bacterial and fungal infections in patients with de novo acute myeloid leukemia (AML) who develop neutropenia while receiving induction chemotherapy.

The FDA grants RMAT designation to therapies intended to treat serious or life-threatening conditions if there is preliminary clinical evidence that the therapies could address unmet medical needs.

RMAT designation provides similar advantages as breakthrough therapy designation, including early interactions with the FDA to discuss potential ways to accelerate the development of a therapy toward regulatory approval.

The FDA granted romyelocel-L RMAT designation based on a randomized, phase 2 trial of newly diagnosed AML patients who received induction consisting of cytarabine and an anthracycline.

Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 7043).

The trial enrolled 163 AML patients and randomized them, on the first day of induction, to receive:

• Daily granulocyte colony-stimulating factor (G-CSF) starting on day 14 (n=84)
• Romyelocel-L (7.5 x 10⁶cells/kg) on day 9 plus daily G-CSF starting on day 14 (n=79).

Patients received G-CSF until neutrophil recovery to at least 500/µL.

Baseline characteristics were well balanced between the treatment arms.

There were 120 evaluable patients—59 in the romyelocel-L arm and 61 in the control arm.

The study’s primary endpoint was days in a febrile episode (DFE). The mean DFE from day 9 to 28 was 6.46 days in the romyelocel-L arm and 6.86 days in the control arm (P=0.350). The mean DFE for days 15 to 28 was 2.36 and 3.90, respectively (P=0.020).

The incidence of microbiologically or clinically diagnosed infection from day 9 to 28 was 35.6% in the romyelocel-L arm and 47.5% in the control arm, a decrease of 25% (P=0.089).

From day 15 to 28 the incidence of infection was 6.8% in the romyelocel-L arm and 27.9% in the control arm, a decrease of 76% (P=0.002).

There were no infectious deaths in the romyelocel-L arm but 2 deaths attributed to pneumonia in the control arm.

The mean hospital stay was 25.5 days in the romyelocel-L arm and 28.7 days in the control arm (P=0.002).

The proportion of patients with serious adverse events (AEs) was 14% in the romyelocel-L arm and 18% in the control arm. The proportion of patients with infectious serious AEs was 50% and 77%, respectively.

The most frequent treatment-emergent AEs (in the romyelocel-L and control arms, respectively) were febrile neutropenia (31.4% and 31%), diarrhea (25.7% and 32.4%), hypokalemia (31.4% and 25.4%), hypophosphatemia (21.4% and 23.9%), and pyrexia (22.9% and 22.5%).

There were no cases of graft-versus-host disease.  

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has granted regenerative medicine advanced therapy (RMAT) designation for romyelocel-L, a myeloid progenitor cell therapy that doesn’t require HLA matching.

Romyelocel-L (CLT-008) is being developed as prophylaxis for serious bacterial and fungal infections in patients with de novo acute myeloid leukemia (AML) who develop neutropenia while receiving induction chemotherapy.

The FDA grants RMAT designation to therapies intended to treat serious or life-threatening conditions if there is preliminary clinical evidence that the therapies could address unmet medical needs.

RMAT designation provides similar advantages as breakthrough therapy designation, including early interactions with the FDA to discuss potential ways to accelerate the development of a therapy toward regulatory approval.

The FDA granted romyelocel-L RMAT designation based on a randomized, phase 2 trial of newly diagnosed AML patients who received induction consisting of cytarabine and an anthracycline.

Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 7043).

The trial enrolled 163 AML patients and randomized them, on the first day of induction, to receive:

• Daily granulocyte colony-stimulating factor (G-CSF) starting on day 14 (n=84)
• Romyelocel-L (7.5 x 10⁶cells/kg) on day 9 plus daily G-CSF starting on day 14 (n=79).

Patients received G-CSF until neutrophil recovery to at least 500/µL.

Baseline characteristics were well balanced between the treatment arms.

There were 120 evaluable patients—59 in the romyelocel-L arm and 61 in the control arm.

The study’s primary endpoint was days in a febrile episode (DFE). The mean DFE from day 9 to 28 was 6.46 days in the romyelocel-L arm and 6.86 days in the control arm (P=0.350). The mean DFE for days 15 to 28 was 2.36 and 3.90, respectively (P=0.020).

The incidence of microbiologically or clinically diagnosed infection from day 9 to 28 was 35.6% in the romyelocel-L arm and 47.5% in the control arm, a decrease of 25% (P=0.089).

From day 15 to 28 the incidence of infection was 6.8% in the romyelocel-L arm and 27.9% in the control arm, a decrease of 76% (P=0.002).

There were no infectious deaths in the romyelocel-L arm but 2 deaths attributed to pneumonia in the control arm.

The mean hospital stay was 25.5 days in the romyelocel-L arm and 28.7 days in the control arm (P=0.002).

The proportion of patients with serious adverse events (AEs) was 14% in the romyelocel-L arm and 18% in the control arm. The proportion of patients with infectious serious AEs was 50% and 77%, respectively.

The most frequent treatment-emergent AEs (in the romyelocel-L and control arms, respectively) were febrile neutropenia (31.4% and 31%), diarrhea (25.7% and 32.4%), hypokalemia (31.4% and 25.4%), hypophosphatemia (21.4% and 23.9%), and pyrexia (22.9% and 22.5%).

There were no cases of graft-versus-host disease.  

The FP diagnosed syringomas in this patient.

He explained that the bumps are benign tumors that occur frequently on the lower eyelids and upper cheeks. They are completely unrelated to the birth control pill and can develop in men, and run in families, too. While syringomas appear to occur more often in women than men, there are no known causative agents. These are benign growths of the eccrine sweat glands.

Treatment options include cryosurgery, electrosurgery, or chemical destruction with trichloroacetic acid. All of these approaches need to be performed carefully, as the syringomas are so close to the eye. Also, these treatments are only modestly effective; new syringomas can form. And there are no preventive treatments.

In this case, the patient had light brown skin, so there was a risk of causing permanent hypopigmentation with any of these destructive methods. The patient was reassured about the benign nature of the condition; she decided not to seek therapy.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith M. Epidermal nevus and nevus sebaceous. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:958-962.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.

The FP diagnosed syringomas in this patient.

He explained that the bumps are benign tumors that occur frequently on the lower eyelids and upper cheeks. They are completely unrelated to the birth control pill and can develop in men, and run in families, too. While syringomas appear to occur more often in women than men, there are no known causative agents. These are benign growths of the eccrine sweat glands.

Treatment options include cryosurgery, electrosurgery, or chemical destruction with trichloroacetic acid. All of these approaches need to be performed carefully, as the syringomas are so close to the eye. Also, these treatments are only modestly effective; new syringomas can form. And there are no preventive treatments.

In this case, the patient had light brown skin, so there was a risk of causing permanent hypopigmentation with any of these destructive methods. The patient was reassured about the benign nature of the condition; she decided not to seek therapy.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith M. Epidermal nevus and nevus sebaceous. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:958-962.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.

The FP diagnosed syringomas in this patient.

He explained that the bumps are benign tumors that occur frequently on the lower eyelids and upper cheeks. They are completely unrelated to the birth control pill and can develop in men, and run in families, too. While syringomas appear to occur more often in women than men, there are no known causative agents. These are benign growths of the eccrine sweat glands.

Treatment options include cryosurgery, electrosurgery, or chemical destruction with trichloroacetic acid. All of these approaches need to be performed carefully, as the syringomas are so close to the eye. Also, these treatments are only modestly effective; new syringomas can form. And there are no preventive treatments.

In this case, the patient had light brown skin, so there was a risk of causing permanent hypopigmentation with any of these destructive methods. The patient was reassured about the benign nature of the condition; she decided not to seek therapy.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith M. Epidermal nevus and nevus sebaceous. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:958-962.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.

During the early days of the American Academy of Nurse Practitioners (incorporated in 1985), I spotted a full-page ad by the Campaign Consultants of America addressed to professional fund­raisers. What caught my eye was a photograph of a mother with the tagline, “There’s only one person who understands you better than we do, and she still doesn’t understand what you do for a living.” I pulled the page from the magazine and made a note to consider using it to promote the NP profession. What we needed at the time, despite being an established profession, was to publicly market our role as experts in health promotion and disease prevention. What we needed was brand recognition.

Historically, branding has been a task undertaken by a company’s marketing department or an advertising agency to identify elements that differentiate their product from the competition’s. Designing a logo, creating a jingle (Oscar-Mayer, anyone?), or recording a sound bite are the means to emphasize the difference. It paints the mental picture people have of a company, a product, or a provider. These cues remind the consumer about the product. So, how does this apply to the NP (and PA) profession?

The importance of establishing a “brand”—of distinguishing ourselves as competent clinicians with a specific skillset to offer the primary care community—cannot be overstated. Personal branding is a key component of fostering patient loyalty, building your reputation, and increasing referrals to your practice. Understanding the needs and desires of patients, their families, and the community is crucial. Our personal brand emphasizes our assets and expertise. While it can be difficult to look at yourself objectively (especially your assets), it is necessary in today’s competitive world of health care.

NPs constitute the fastest-growing segment of the primary care workforce in the US. More than 50 years of transforming health care as we know it has made us indispensable as health care providers. The literature has long supported the position that NPs provide care that is effective, patient-centered, and evidenced-based. Who we are, what we do, and how well we do it has been documented in myriad reports, surveys, and publications. Yet in many ways, we continue to struggle with an in-between identity. Despite our increasing responsibility in the clinical realm, some are still confused as to who we are.

We are known as nurses first, yet much of the health care we now provide was traditionally in the “physician-only” domain. And because of that history, our ability to function to the fullest extent of our education has been hobbled. These practice restrictions are counterproductive at a time when our nation is facing serious public health challenges.

Over the years, barriers to practice have slowly been whittled away, but full appreciation and recognition of our professional excellence and our contribution to improve the nation’s health is lacking. The fact that much of the research on health status and health ranking fails to include NPs and PAs is testimony that we remain somewhat invisible. And that, my friends, is exactly why it is time to revisit that aforementioned advertisement—not because our mothers don’t know what we do, but because, to some degree, we have eased off the belief that there are still obstacles to full access to NPs as primary care providers. And that is the origin of the need to establish your own brand.

Creating and maintaining your personal brand necessitates that you be multi-functional. You must be a role model, a mentor, and a voice that is respected and reliable. Your brand should advertise what you are known for and what motivates people to seek you, specifically, for their health care needs. Be relentlessly focused on what you do that adds value. As NPs, we have a unique blend of nursing and medicine that allows us to provide the patient-centered care that is central to meeting the existing and future primary care needs of our nation. From our roots in nursing, we offer patients high-quality care and a provider to partner with them in developing their plan of care.

Continue to: A foundational component of building your brand is...

A foundational component of building your brand is positioning yourself as a credible expert and leader. We each have a unique collection of experiences in preventive and primary care. Share that experience by getting involved in your community: participate in health fairs, interact with local news media, or volunteer to serve on your local health board. Emphasize the quality, flexibility, and continuity of care that you can provide. Share any survey findings that demonstrate your ability to anticipate, meet, and even exceed patients’ needs. Demonstrate your ability to deliver quality, accessible health care in a diverse society with increasingly complex medical needs.

As the nation continues to face a shortage of primary care providers and services—a gap that NPs and PAs are equipped to fill—it’s time for us to promote ourselves and advertise all that we can do. This isn’t just for our own sakes, but for our patients’ as well. Give some serious thought (and even more serious effort) to imagining and developing yourself as a brand. Define your brand’s attributes and the qualities or characteristics that make you distinctive from your competitors (or even your colleagues). You are the CEO of brand YOU!

If you have examples of how you promote your personal brand, please share them with me at [email protected].

During the early days of the American Academy of Nurse Practitioners (incorporated in 1985), I spotted a full-page ad by the Campaign Consultants of America addressed to professional fund­raisers. What caught my eye was a photograph of a mother with the tagline, “There’s only one person who understands you better than we do, and she still doesn’t understand what you do for a living.” I pulled the page from the magazine and made a note to consider using it to promote the NP profession. What we needed at the time, despite being an established profession, was to publicly market our role as experts in health promotion and disease prevention. What we needed was brand recognition.

Historically, branding has been a task undertaken by a company’s marketing department or an advertising agency to identify elements that differentiate their product from the competition’s. Designing a logo, creating a jingle (Oscar-Mayer, anyone?), or recording a sound bite are the means to emphasize the difference. It paints the mental picture people have of a company, a product, or a provider. These cues remind the consumer about the product. So, how does this apply to the NP (and PA) profession?

The importance of establishing a “brand”—of distinguishing ourselves as competent clinicians with a specific skillset to offer the primary care community—cannot be overstated. Personal branding is a key component of fostering patient loyalty, building your reputation, and increasing referrals to your practice. Understanding the needs and desires of patients, their families, and the community is crucial. Our personal brand emphasizes our assets and expertise. While it can be difficult to look at yourself objectively (especially your assets), it is necessary in today’s competitive world of health care.

NPs constitute the fastest-growing segment of the primary care workforce in the US. More than 50 years of transforming health care as we know it has made us indispensable as health care providers. The literature has long supported the position that NPs provide care that is effective, patient-centered, and evidenced-based. Who we are, what we do, and how well we do it has been documented in myriad reports, surveys, and publications. Yet in many ways, we continue to struggle with an in-between identity. Despite our increasing responsibility in the clinical realm, some are still confused as to who we are.

We are known as nurses first, yet much of the health care we now provide was traditionally in the “physician-only” domain. And because of that history, our ability to function to the fullest extent of our education has been hobbled. These practice restrictions are counterproductive at a time when our nation is facing serious public health challenges.

Over the years, barriers to practice have slowly been whittled away, but full appreciation and recognition of our professional excellence and our contribution to improve the nation’s health is lacking. The fact that much of the research on health status and health ranking fails to include NPs and PAs is testimony that we remain somewhat invisible. And that, my friends, is exactly why it is time to revisit that aforementioned advertisement—not because our mothers don’t know what we do, but because, to some degree, we have eased off the belief that there are still obstacles to full access to NPs as primary care providers. And that is the origin of the need to establish your own brand.

Creating and maintaining your personal brand necessitates that you be multi-functional. You must be a role model, a mentor, and a voice that is respected and reliable. Your brand should advertise what you are known for and what motivates people to seek you, specifically, for their health care needs. Be relentlessly focused on what you do that adds value. As NPs, we have a unique blend of nursing and medicine that allows us to provide the patient-centered care that is central to meeting the existing and future primary care needs of our nation. From our roots in nursing, we offer patients high-quality care and a provider to partner with them in developing their plan of care.

Continue to: A foundational component of building your brand is...

A foundational component of building your brand is positioning yourself as a credible expert and leader. We each have a unique collection of experiences in preventive and primary care. Share that experience by getting involved in your community: participate in health fairs, interact with local news media, or volunteer to serve on your local health board. Emphasize the quality, flexibility, and continuity of care that you can provide. Share any survey findings that demonstrate your ability to anticipate, meet, and even exceed patients’ needs. Demonstrate your ability to deliver quality, accessible health care in a diverse society with increasingly complex medical needs.

As the nation continues to face a shortage of primary care providers and services—a gap that NPs and PAs are equipped to fill—it’s time for us to promote ourselves and advertise all that we can do. This isn’t just for our own sakes, but for our patients’ as well. Give some serious thought (and even more serious effort) to imagining and developing yourself as a brand. Define your brand’s attributes and the qualities or characteristics that make you distinctive from your competitors (or even your colleagues). You are the CEO of brand YOU!

If you have examples of how you promote your personal brand, please share them with me at [email protected].

During the early days of the American Academy of Nurse Practitioners (incorporated in 1985), I spotted a full-page ad by the Campaign Consultants of America addressed to professional fund­raisers. What caught my eye was a photograph of a mother with the tagline, “There’s only one person who understands you better than we do, and she still doesn’t understand what you do for a living.” I pulled the page from the magazine and made a note to consider using it to promote the NP profession. What we needed at the time, despite being an established profession, was to publicly market our role as experts in health promotion and disease prevention. What we needed was brand recognition.

Historically, branding has been a task undertaken by a company’s marketing department or an advertising agency to identify elements that differentiate their product from the competition’s. Designing a logo, creating a jingle (Oscar-Mayer, anyone?), or recording a sound bite are the means to emphasize the difference. It paints the mental picture people have of a company, a product, or a provider. These cues remind the consumer about the product. So, how does this apply to the NP (and PA) profession?

The importance of establishing a “brand”—of distinguishing ourselves as competent clinicians with a specific skillset to offer the primary care community—cannot be overstated. Personal branding is a key component of fostering patient loyalty, building your reputation, and increasing referrals to your practice. Understanding the needs and desires of patients, their families, and the community is crucial. Our personal brand emphasizes our assets and expertise. While it can be difficult to look at yourself objectively (especially your assets), it is necessary in today’s competitive world of health care.

NPs constitute the fastest-growing segment of the primary care workforce in the US. More than 50 years of transforming health care as we know it has made us indispensable as health care providers. The literature has long supported the position that NPs provide care that is effective, patient-centered, and evidenced-based. Who we are, what we do, and how well we do it has been documented in myriad reports, surveys, and publications. Yet in many ways, we continue to struggle with an in-between identity. Despite our increasing responsibility in the clinical realm, some are still confused as to who we are.

We are known as nurses first, yet much of the health care we now provide was traditionally in the “physician-only” domain. And because of that history, our ability to function to the fullest extent of our education has been hobbled. These practice restrictions are counterproductive at a time when our nation is facing serious public health challenges.

Over the years, barriers to practice have slowly been whittled away, but full appreciation and recognition of our professional excellence and our contribution to improve the nation’s health is lacking. The fact that much of the research on health status and health ranking fails to include NPs and PAs is testimony that we remain somewhat invisible. And that, my friends, is exactly why it is time to revisit that aforementioned advertisement—not because our mothers don’t know what we do, but because, to some degree, we have eased off the belief that there are still obstacles to full access to NPs as primary care providers. And that is the origin of the need to establish your own brand.

Creating and maintaining your personal brand necessitates that you be multi-functional. You must be a role model, a mentor, and a voice that is respected and reliable. Your brand should advertise what you are known for and what motivates people to seek you, specifically, for their health care needs. Be relentlessly focused on what you do that adds value. As NPs, we have a unique blend of nursing and medicine that allows us to provide the patient-centered care that is central to meeting the existing and future primary care needs of our nation. From our roots in nursing, we offer patients high-quality care and a provider to partner with them in developing their plan of care.

Continue to: A foundational component of building your brand is...

A foundational component of building your brand is positioning yourself as a credible expert and leader. We each have a unique collection of experiences in preventive and primary care. Share that experience by getting involved in your community: participate in health fairs, interact with local news media, or volunteer to serve on your local health board. Emphasize the quality, flexibility, and continuity of care that you can provide. Share any survey findings that demonstrate your ability to anticipate, meet, and even exceed patients’ needs. Demonstrate your ability to deliver quality, accessible health care in a diverse society with increasingly complex medical needs.

As the nation continues to face a shortage of primary care providers and services—a gap that NPs and PAs are equipped to fill—it’s time for us to promote ourselves and advertise all that we can do. This isn’t just for our own sakes, but for our patients’ as well. Give some serious thought (and even more serious effort) to imagining and developing yourself as a brand. Define your brand’s attributes and the qualities or characteristics that make you distinctive from your competitors (or even your colleagues). You are the CEO of brand YOU!

If you have examples of how you promote your personal brand, please share them with me at [email protected].

Preoperative physiotherapy reduces postoperative pulmonary complications in patients undergoing elective abdominal surgery

A randomized, controlled trial showed that, in patients having elective abdominal surgery, a 30-minute preoperative physiotherapy session – that focused on breathing exercise training and education – reduced postoperative pulmonary complications, including hospital-acquired pneumonia, by half (hazard ratio, 0.48; number needed to treat, seven).

Severity of thrombocytopenia does not predict bleeding risk in patients with cirrhosis

A subgroup analysis of a prospective cohort study showed that, although platelet counts worsened with progression of liver disease, platelet counts were similar in patients with and without a bleeding event.

Citation: Basili S et al. Platelet count does not predict bleeding in cirrhotic patients: Results from the PRO-LIVER study. Am J Gastroenterol. 2018 Mar;113(3):368-75.

Patent foramen ovale closures are superior to medical therapy in patients with medium to large PFOs

A meta-analysis of four randomized, controlled trials found that patients with cryptogenic stroke who underwent PFO closure had decreased rates of stroke and transient ischemic attack, compared with medical therapy alone, but had increased incidence of atrial fibrillation or atrial flutter.

Citation: De Rosa S et al. Percutaneous closure versus medical treatment in stroke patients with patent foramen ovale: A systematic review and meta-analysis. Ann Intern Med. 2018 Mar 6;168(5):343-50.

Short-run atrial tachyarrhythmias increase the risk of stroke

A retrospective, observational study showed that patients with short-run atrial tachyarrhythmias (more than three consecutive supraventricular ectopic beats lasting less than 5 seconds) have an increased risk of stroke (11.4% vs. 8.3%; P
Citation: Yamada S et al. Risk of stroke in patients with short-run atrial tachyarrhythmia. Stroke. 2017 Dec;48(12):3232-8.

Even one cigarette is too many

A meta-analysis of 55 publications containing 141 cohort studies demonstrated that even those that smoked one cigarette per day were at increased risk of developing coronary artery disease and stroke.

Citation: Hackshaw A et al. Low cigarette consumption and risk of coronary heart disease and stroke: Meta-analysis of 141 cohort studies in 55 study reports. BMJ. 2018 Jan 24;360:j5855.

Preoperative physiotherapy reduces postoperative pulmonary complications in patients undergoing elective abdominal surgery

A randomized, controlled trial showed that, in patients having elective abdominal surgery, a 30-minute preoperative physiotherapy session – that focused on breathing exercise training and education – reduced postoperative pulmonary complications, including hospital-acquired pneumonia, by half (hazard ratio, 0.48; number needed to treat, seven).

Severity of thrombocytopenia does not predict bleeding risk in patients with cirrhosis

A subgroup analysis of a prospective cohort study showed that, although platelet counts worsened with progression of liver disease, platelet counts were similar in patients with and without a bleeding event.

Citation: Basili S et al. Platelet count does not predict bleeding in cirrhotic patients: Results from the PRO-LIVER study. Am J Gastroenterol. 2018 Mar;113(3):368-75.

Patent foramen ovale closures are superior to medical therapy in patients with medium to large PFOs

A meta-analysis of four randomized, controlled trials found that patients with cryptogenic stroke who underwent PFO closure had decreased rates of stroke and transient ischemic attack, compared with medical therapy alone, but had increased incidence of atrial fibrillation or atrial flutter.

Citation: De Rosa S et al. Percutaneous closure versus medical treatment in stroke patients with patent foramen ovale: A systematic review and meta-analysis. Ann Intern Med. 2018 Mar 6;168(5):343-50.

Short-run atrial tachyarrhythmias increase the risk of stroke

A retrospective, observational study showed that patients with short-run atrial tachyarrhythmias (more than three consecutive supraventricular ectopic beats lasting less than 5 seconds) have an increased risk of stroke (11.4% vs. 8.3%; P
Citation: Yamada S et al. Risk of stroke in patients with short-run atrial tachyarrhythmia. Stroke. 2017 Dec;48(12):3232-8.

Even one cigarette is too many

A meta-analysis of 55 publications containing 141 cohort studies demonstrated that even those that smoked one cigarette per day were at increased risk of developing coronary artery disease and stroke.

Citation: Hackshaw A et al. Low cigarette consumption and risk of coronary heart disease and stroke: Meta-analysis of 141 cohort studies in 55 study reports. BMJ. 2018 Jan 24;360:j5855.

Preoperative physiotherapy reduces postoperative pulmonary complications in patients undergoing elective abdominal surgery

A randomized, controlled trial showed that, in patients having elective abdominal surgery, a 30-minute preoperative physiotherapy session – that focused on breathing exercise training and education – reduced postoperative pulmonary complications, including hospital-acquired pneumonia, by half (hazard ratio, 0.48; number needed to treat, seven).

Severity of thrombocytopenia does not predict bleeding risk in patients with cirrhosis

A subgroup analysis of a prospective cohort study showed that, although platelet counts worsened with progression of liver disease, platelet counts were similar in patients with and without a bleeding event.

Citation: Basili S et al. Platelet count does not predict bleeding in cirrhotic patients: Results from the PRO-LIVER study. Am J Gastroenterol. 2018 Mar;113(3):368-75.

Patent foramen ovale closures are superior to medical therapy in patients with medium to large PFOs

A meta-analysis of four randomized, controlled trials found that patients with cryptogenic stroke who underwent PFO closure had decreased rates of stroke and transient ischemic attack, compared with medical therapy alone, but had increased incidence of atrial fibrillation or atrial flutter.

Citation: De Rosa S et al. Percutaneous closure versus medical treatment in stroke patients with patent foramen ovale: A systematic review and meta-analysis. Ann Intern Med. 2018 Mar 6;168(5):343-50.

Short-run atrial tachyarrhythmias increase the risk of stroke

A retrospective, observational study showed that patients with short-run atrial tachyarrhythmias (more than three consecutive supraventricular ectopic beats lasting less than 5 seconds) have an increased risk of stroke (11.4% vs. 8.3%; P
Citation: Yamada S et al. Risk of stroke in patients with short-run atrial tachyarrhythmia. Stroke. 2017 Dec;48(12):3232-8.

Even one cigarette is too many

A meta-analysis of 55 publications containing 141 cohort studies demonstrated that even those that smoked one cigarette per day were at increased risk of developing coronary artery disease and stroke.

Citation: Hackshaw A et al. Low cigarette consumption and risk of coronary heart disease and stroke: Meta-analysis of 141 cohort studies in 55 study reports. BMJ. 2018 Jan 24;360:j5855.

Tecovirimat, an oral antiviral agent, is being advanced as a treatment for smallpox based on recently reported studies showing efficacy data in animals and safety and pharmacokinetic data in humans.

“The aggregation of the results from these multiple studies involving animals and humans supports tecovirimat as potential smallpox antiviral drug,” Douglas W. Grosenbach, PhD, of SIGA Technologies and his coauthors reported in the New England Journal of Medicine.

Tecovirimat inhibits p37, a protein that is present in all orthopoxviruses, to prevent “formation and egress of enveloped virions, which are essential for virulence,” Dr. Grosenbach and his coauthors wrote in the report.

Smallpox, caused by the variola virus, was eradicated in 1980. However, the disease remains concerning because of the potential for intentional release of variola virus in an act of bioterrorism or biowarfare, according to the authors.

“A single case of smallpox anywhere in the world would be a global health emergency,” Dr. Grosenbach and his colleagues wrote.

Available vaccines are not used because of the risk of side effects and would not be used except in the case of known or suspected variola virus exposure, they added.

Since it would be unethical to intentionally expose humans to variola virus, tecovirimat is being developed in line with the Food and Drug Administration Animal Efficacy Rule, which gives the agency the authority to approve drugs based on animal data for diseases that have a low or nonexistent rate of natural occurrence.

The first treatment developed under the Animal Efficacy Rule, was raxibacumab, a biologic approved by the FDA in December 2012 for treatment of inhalation anthrax. Subsequently, several other agents for prophylaxis or treatment of anthrax and botulism have been developed based on the rule and approved.

Tecovirimat has demonstrated protective efficacy in pilot studies conducted in rabbits infected with rabbitpox virus and nonhuman primates infected with monkeypox virus, Dr. Grosenbach and his colleagues explained in the current report.

In nonhuman primate studies, doses of 3-10 mg/kilogram provided nearly full protection from death with a survival rate of approximately 95% versus 5% for placebo, along with reduced lesion counts and viral loads, according to investigators.

In a tecovirimat clinical trial, 452 volunteers were randomized to receive the antiviral agent twice daily at 600 mg or matching placebo for 14 days. Adverse events occurred in 37.3% of tecovirimat-treated and 33.3% of placebo-treated participants, with events of grade 3 or higher occurring in 1.1% of patients in both groups.

There was one death on the tecovirimat arm, which was caused by a pulmonary embolism in a participant who had a history of recurrent deep-vein thrombosis but was not receiving anticoagulant treatment, investigators said.

Dr. Grosenbach and colleagues also presented pharmacokinetic profiles and exposures for 48 volunteers in a fed state in their report in the New England Journal of Medicine, along with pharmacokinetic data from the animal studies.

The FDA has set a target date of Aug. 8, 2018, for final action on a new drug application submitted for oral tecovirimat for treatment of smallpox, SIGA Technologies said in a May 2018 news release.

SOURCE: Grosenbach DW et al. N Engl J Med. 2018 Jul 5;379(1):44-53.

Tecovirimat, an oral antiviral agent, is being advanced as a treatment for smallpox based on recently reported studies showing efficacy data in animals and safety and pharmacokinetic data in humans.

“The aggregation of the results from these multiple studies involving animals and humans supports tecovirimat as potential smallpox antiviral drug,” Douglas W. Grosenbach, PhD, of SIGA Technologies and his coauthors reported in the New England Journal of Medicine.

Tecovirimat inhibits p37, a protein that is present in all orthopoxviruses, to prevent “formation and egress of enveloped virions, which are essential for virulence,” Dr. Grosenbach and his coauthors wrote in the report.

Smallpox, caused by the variola virus, was eradicated in 1980. However, the disease remains concerning because of the potential for intentional release of variola virus in an act of bioterrorism or biowarfare, according to the authors.

“A single case of smallpox anywhere in the world would be a global health emergency,” Dr. Grosenbach and his colleagues wrote.

Available vaccines are not used because of the risk of side effects and would not be used except in the case of known or suspected variola virus exposure, they added.

Since it would be unethical to intentionally expose humans to variola virus, tecovirimat is being developed in line with the Food and Drug Administration Animal Efficacy Rule, which gives the agency the authority to approve drugs based on animal data for diseases that have a low or nonexistent rate of natural occurrence.

The first treatment developed under the Animal Efficacy Rule, was raxibacumab, a biologic approved by the FDA in December 2012 for treatment of inhalation anthrax. Subsequently, several other agents for prophylaxis or treatment of anthrax and botulism have been developed based on the rule and approved.

Tecovirimat has demonstrated protective efficacy in pilot studies conducted in rabbits infected with rabbitpox virus and nonhuman primates infected with monkeypox virus, Dr. Grosenbach and his colleagues explained in the current report.

In nonhuman primate studies, doses of 3-10 mg/kilogram provided nearly full protection from death with a survival rate of approximately 95% versus 5% for placebo, along with reduced lesion counts and viral loads, according to investigators.

In a tecovirimat clinical trial, 452 volunteers were randomized to receive the antiviral agent twice daily at 600 mg or matching placebo for 14 days. Adverse events occurred in 37.3% of tecovirimat-treated and 33.3% of placebo-treated participants, with events of grade 3 or higher occurring in 1.1% of patients in both groups.

There was one death on the tecovirimat arm, which was caused by a pulmonary embolism in a participant who had a history of recurrent deep-vein thrombosis but was not receiving anticoagulant treatment, investigators said.

Dr. Grosenbach and colleagues also presented pharmacokinetic profiles and exposures for 48 volunteers in a fed state in their report in the New England Journal of Medicine, along with pharmacokinetic data from the animal studies.

The FDA has set a target date of Aug. 8, 2018, for final action on a new drug application submitted for oral tecovirimat for treatment of smallpox, SIGA Technologies said in a May 2018 news release.

SOURCE: Grosenbach DW et al. N Engl J Med. 2018 Jul 5;379(1):44-53.

Tecovirimat, an oral antiviral agent, is being advanced as a treatment for smallpox based on recently reported studies showing efficacy data in animals and safety and pharmacokinetic data in humans.

“The aggregation of the results from these multiple studies involving animals and humans supports tecovirimat as potential smallpox antiviral drug,” Douglas W. Grosenbach, PhD, of SIGA Technologies and his coauthors reported in the New England Journal of Medicine.

Tecovirimat inhibits p37, a protein that is present in all orthopoxviruses, to prevent “formation and egress of enveloped virions, which are essential for virulence,” Dr. Grosenbach and his coauthors wrote in the report.

Smallpox, caused by the variola virus, was eradicated in 1980. However, the disease remains concerning because of the potential for intentional release of variola virus in an act of bioterrorism or biowarfare, according to the authors.

“A single case of smallpox anywhere in the world would be a global health emergency,” Dr. Grosenbach and his colleagues wrote.

Available vaccines are not used because of the risk of side effects and would not be used except in the case of known or suspected variola virus exposure, they added.

Since it would be unethical to intentionally expose humans to variola virus, tecovirimat is being developed in line with the Food and Drug Administration Animal Efficacy Rule, which gives the agency the authority to approve drugs based on animal data for diseases that have a low or nonexistent rate of natural occurrence.

The first treatment developed under the Animal Efficacy Rule, was raxibacumab, a biologic approved by the FDA in December 2012 for treatment of inhalation anthrax. Subsequently, several other agents for prophylaxis or treatment of anthrax and botulism have been developed based on the rule and approved.

Tecovirimat has demonstrated protective efficacy in pilot studies conducted in rabbits infected with rabbitpox virus and nonhuman primates infected with monkeypox virus, Dr. Grosenbach and his colleagues explained in the current report.

In nonhuman primate studies, doses of 3-10 mg/kilogram provided nearly full protection from death with a survival rate of approximately 95% versus 5% for placebo, along with reduced lesion counts and viral loads, according to investigators.

In a tecovirimat clinical trial, 452 volunteers were randomized to receive the antiviral agent twice daily at 600 mg or matching placebo for 14 days. Adverse events occurred in 37.3% of tecovirimat-treated and 33.3% of placebo-treated participants, with events of grade 3 or higher occurring in 1.1% of patients in both groups.

There was one death on the tecovirimat arm, which was caused by a pulmonary embolism in a participant who had a history of recurrent deep-vein thrombosis but was not receiving anticoagulant treatment, investigators said.

Dr. Grosenbach and colleagues also presented pharmacokinetic profiles and exposures for 48 volunteers in a fed state in their report in the New England Journal of Medicine, along with pharmacokinetic data from the animal studies.

The FDA has set a target date of Aug. 8, 2018, for final action on a new drug application submitted for oral tecovirimat for treatment of smallpox, SIGA Technologies said in a May 2018 news release.

SOURCE: Grosenbach DW et al. N Engl J Med. 2018 Jul 5;379(1):44-53.